Author: "Svendsen, Clive N." / Database: OAIster - Searchworks@Jio Institute Digital Library Search Results

Your search keyword '"Svendsen, Clive N."' showing total 40 results

Start Over Author "Svendsen, Clive N." Database OAIster

40 results on '"Svendsen, Clive N."'

1. NeuroLINCS Proteomics: Defining human-derived iPSC proteomes and protein signatures of pluripotency.

Author: Matlock, Andrea D, Matlock, Andrea D, Vaibhav, Vineet, Holewinski, Ronald, Venkatraman, Vidya, Dardov, Victoria, Manalo, Danica-Mae, Shelley, Brandon, Ornelas, Loren, Banuelos, Maria, Mandefro, Berhan, Escalante-Chong, Renan, Li, Jonathan, Finkbeiner, Steve, Fraenkel, Ernest, Rothstein, Jeffrey, Thompson, Leslie, Sareen, Dhruv, Svendsen, Clive N, NIH NeuroLINCS Consortium, Van Eyk, Jennifer E, Matlock, Andrea D, Matlock, Andrea D, Vaibhav, Vineet, Holewinski, Ronald, Venkatraman, Vidya, Dardov, Victoria, Manalo, Danica-Mae, Shelley, Brandon, Ornelas, Loren, Banuelos, Maria, Mandefro, Berhan, Escalante-Chong, Renan, Li, Jonathan, Finkbeiner, Steve, Fraenkel, Ernest, Rothstein, Jeffrey, Thompson, Leslie, Sareen, Dhruv, Svendsen, Clive N, NIH NeuroLINCS Consortium, and Van Eyk, Jennifer E
Abstract: The National Institute of Health (NIH) Library of integrated network-based cellular signatures (LINCS) program is premised on the generation of a publicly available data resource of cell-based biochemical responses or "signatures" to genetic or environmental perturbations. NeuroLINCS uses human inducible pluripotent stem cells (hiPSCs), derived from patients and healthy controls, and differentiated into motor neuron cell cultures. This multi-laboratory effort strives to establish i) robust multi-omic workflows for hiPSC and differentiated neuronal cultures, ii) public annotated data sets and iii) relevant and targetable biological pathways of spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS). Here, we focus on the proteomics and the quality of the developed workflow of hiPSC lines from 6 individuals, though epigenomics and transcriptomics data are also publicly available. Known and commonly used markers representing 73 proteins were reproducibly quantified with consistent expression levels across all hiPSC lines. Data quality assessments, data levels and metadata of all 6 genetically diverse human iPSCs analysed by DIA-MS are parsable and available as a high-quality resource to the public.
Published: 2023

2. Answer ALS, a large-scale resource for sporadic and familial ALS combining clinical and multi-omics data from induced pluripotent cell lines.

Author: Baxi, Emily G, Baxi, Emily G, Thompson, Terri, Li, Jonathan, Kaye, Julia A, Lim, Ryan G, Wu, Jie, Ramamoorthy, Divya, Lima, Leandro, Vaibhav, Vineet, Matlock, Andrea, Frank, Aaron, Coyne, Alyssa N, Landin, Barry, Ornelas, Loren, Mosmiller, Elizabeth, Thrower, Sara, Farr, S Michelle, Panther, Lindsey, Gomez, Emilda, Galvez, Erick, Perez, Daniel, Meepe, Imara, Lei, Susan, Mandefro, Berhan, Trost, Hannah, Pinedo, Louis, Banuelos, Maria G, Liu, Chunyan, Moran, Ruby, Garcia, Veronica, Workman, Michael, Ho, Richie, Wyman, Stacia, Roggenbuck, Jennifer, Harms, Matthew B, Stocksdale, Jennifer, Miramontes, Ricardo, Wang, Keona, Venkatraman, Vidya, Holewenski, Ronald, Sundararaman, Niveda, Pandey, Rakhi, Manalo, Danica-Mae, Donde, Aneesh, Huynh, Nhan, Adam, Miriam, Wassie, Brook T, Vertudes, Edward, Amirani, Naufa, Raja, Krishna, Thomas, Reuben, Hayes, Lindsey, Lenail, Alex, Cerezo, Aianna, Luppino, Sarah, Farrar, Alanna, Pothier, Lindsay, Prina, Carolyn, Morgan, Todd, Jamil, Arish, Heintzman, Sarah, Jockel-Balsarotti, Jennifer, Karanja, Elizabeth, Markway, Jesse, McCallum, Molly, Joslin, Ben, Alibazoglu, Deniz, Kolb, Stephen, Ajroud-Driss, Senda, Baloh, Robert, Heitzman, Daragh, Miller, Tim, Glass, Jonathan D, Patel-Murray, Natasha Leanna, Yu, Hong, Sinani, Ervin, Vigneswaran, Prasha, Sherman, Alexander V, Ahmad, Omar, Roy, Promit, Beavers, Jay C, Zeiler, Steven, Krakauer, John W, Agurto, Carla, Cecchi, Guillermo, Bellard, Mary, Raghav, Yogindra, Sachs, Karen, Ehrenberger, Tobias, Bruce, Elizabeth, Cudkowicz, Merit E, Maragakis, Nicholas, Norel, Raquel, Van Eyk, Jennifer E, Finkbeiner, Steven, Berry, James, Sareen, Dhruv, Thompson, Leslie M, Fraenkel, Ernest, Svendsen, Clive N, Baxi, Emily G, Baxi, Emily G, Thompson, Terri, Li, Jonathan, Kaye, Julia A, Lim, Ryan G, Wu, Jie, Ramamoorthy, Divya, Lima, Leandro, Vaibhav, Vineet, Matlock, Andrea, Frank, Aaron, Coyne, Alyssa N, Landin, Barry, Ornelas, Loren, Mosmiller, Elizabeth, Thrower, Sara, Farr, S Michelle, Panther, Lindsey, Gomez, Emilda, Galvez, Erick, Perez, Daniel, Meepe, Imara, Lei, Susan, Mandefro, Berhan, Trost, Hannah, Pinedo, Louis, Banuelos, Maria G, Liu, Chunyan, Moran, Ruby, Garcia, Veronica, Workman, Michael, Ho, Richie, Wyman, Stacia, Roggenbuck, Jennifer, Harms, Matthew B, Stocksdale, Jennifer, Miramontes, Ricardo, Wang, Keona, Venkatraman, Vidya, Holewenski, Ronald, Sundararaman, Niveda, Pandey, Rakhi, Manalo, Danica-Mae, Donde, Aneesh, Huynh, Nhan, Adam, Miriam, Wassie, Brook T, Vertudes, Edward, Amirani, Naufa, Raja, Krishna, Thomas, Reuben, Hayes, Lindsey, Lenail, Alex, Cerezo, Aianna, Luppino, Sarah, Farrar, Alanna, Pothier, Lindsay, Prina, Carolyn, Morgan, Todd, Jamil, Arish, Heintzman, Sarah, Jockel-Balsarotti, Jennifer, Karanja, Elizabeth, Markway, Jesse, McCallum, Molly, Joslin, Ben, Alibazoglu, Deniz, Kolb, Stephen, Ajroud-Driss, Senda, Baloh, Robert, Heitzman, Daragh, Miller, Tim, Glass, Jonathan D, Patel-Murray, Natasha Leanna, Yu, Hong, Sinani, Ervin, Vigneswaran, Prasha, Sherman, Alexander V, Ahmad, Omar, Roy, Promit, Beavers, Jay C, Zeiler, Steven, Krakauer, John W, Agurto, Carla, Cecchi, Guillermo, Bellard, Mary, Raghav, Yogindra, Sachs, Karen, Ehrenberger, Tobias, Bruce, Elizabeth, Cudkowicz, Merit E, Maragakis, Nicholas, Norel, Raquel, Van Eyk, Jennifer E, Finkbeiner, Steven, Berry, James, Sareen, Dhruv, Thompson, Leslie M, Fraenkel, Ernest, and Svendsen, Clive N
Abstract: Answer ALS is a biological and clinical resource of patient-derived, induced pluripotent stem (iPS) cell lines, multi-omic data derived from iPS neurons and longitudinal clinical and smartphone data from over 1,000 patients with ALS. This resource provides population-level biological and clinical data that may be employed to identify clinical-molecular-biochemical subtypes of amyotrophic lateral sclerosis (ALS). A unique smartphone-based system was employed to collect deep clinical data, including fine motor activity, speech, breathing and linguistics/cognition. The iPS spinal neurons were blood derived from each patient and these cells underwent multi-omic analytics including whole-genome sequencing, RNA transcriptomics, ATAC-sequencing and proteomics. The intent of these data is for the generation of integrated clinical and biological signatures using bioinformatics, statistics and computational biology to establish patterns that may lead to a better understanding of the underlying mechanisms of disease, including subgroup identification. A web portal for open-source sharing of all data was developed for widespread community-based data analytics.
Published: 2022

3. Answer ALS, a large-scale resource for sporadic and familial ALS combining clinical and multi-omics data from induced pluripotent cell lines.

Author: Baxi, Emily G, Baxi, Emily G, Thompson, Terri, Li, Jonathan, Kaye, Julia A, Lim, Ryan G, Wu, Jie, Ramamoorthy, Divya, Lima, Leandro, Vaibhav, Vineet, Matlock, Andrea, Frank, Aaron, Coyne, Alyssa N, Landin, Barry, Ornelas, Loren, Mosmiller, Elizabeth, Thrower, Sara, Farr, S Michelle, Panther, Lindsey, Gomez, Emilda, Galvez, Erick, Perez, Daniel, Meepe, Imara, Lei, Susan, Mandefro, Berhan, Trost, Hannah, Pinedo, Louis, Banuelos, Maria G, Liu, Chunyan, Moran, Ruby, Garcia, Veronica, Workman, Michael, Ho, Richie, Wyman, Stacia, Roggenbuck, Jennifer, Harms, Matthew B, Stocksdale, Jennifer, Miramontes, Ricardo, Wang, Keona, Venkatraman, Vidya, Holewenski, Ronald, Sundararaman, Niveda, Pandey, Rakhi, Manalo, Danica-Mae, Donde, Aneesh, Huynh, Nhan, Adam, Miriam, Wassie, Brook T, Vertudes, Edward, Amirani, Naufa, Raja, Krishna, Thomas, Reuben, Hayes, Lindsey, Lenail, Alex, Cerezo, Aianna, Luppino, Sarah, Farrar, Alanna, Pothier, Lindsay, Prina, Carolyn, Morgan, Todd, Jamil, Arish, Heintzman, Sarah, Jockel-Balsarotti, Jennifer, Karanja, Elizabeth, Markway, Jesse, McCallum, Molly, Joslin, Ben, Alibazoglu, Deniz, Kolb, Stephen, Ajroud-Driss, Senda, Baloh, Robert, Heitzman, Daragh, Miller, Tim, Glass, Jonathan D, Patel-Murray, Natasha Leanna, Yu, Hong, Sinani, Ervin, Vigneswaran, Prasha, Sherman, Alexander V, Ahmad, Omar, Roy, Promit, Beavers, Jay C, Zeiler, Steven, Krakauer, John W, Agurto, Carla, Cecchi, Guillermo, Bellard, Mary, Raghav, Yogindra, Sachs, Karen, Ehrenberger, Tobias, Bruce, Elizabeth, Cudkowicz, Merit E, Maragakis, Nicholas, Norel, Raquel, Van Eyk, Jennifer E, Finkbeiner, Steven, Berry, James, Sareen, Dhruv, Thompson, Leslie M, Fraenkel, Ernest, Svendsen, Clive N, Baxi, Emily G, Baxi, Emily G, Thompson, Terri, Li, Jonathan, Kaye, Julia A, Lim, Ryan G, Wu, Jie, Ramamoorthy, Divya, Lima, Leandro, Vaibhav, Vineet, Matlock, Andrea, Frank, Aaron, Coyne, Alyssa N, Landin, Barry, Ornelas, Loren, Mosmiller, Elizabeth, Thrower, Sara, Farr, S Michelle, Panther, Lindsey, Gomez, Emilda, Galvez, Erick, Perez, Daniel, Meepe, Imara, Lei, Susan, Mandefro, Berhan, Trost, Hannah, Pinedo, Louis, Banuelos, Maria G, Liu, Chunyan, Moran, Ruby, Garcia, Veronica, Workman, Michael, Ho, Richie, Wyman, Stacia, Roggenbuck, Jennifer, Harms, Matthew B, Stocksdale, Jennifer, Miramontes, Ricardo, Wang, Keona, Venkatraman, Vidya, Holewenski, Ronald, Sundararaman, Niveda, Pandey, Rakhi, Manalo, Danica-Mae, Donde, Aneesh, Huynh, Nhan, Adam, Miriam, Wassie, Brook T, Vertudes, Edward, Amirani, Naufa, Raja, Krishna, Thomas, Reuben, Hayes, Lindsey, Lenail, Alex, Cerezo, Aianna, Luppino, Sarah, Farrar, Alanna, Pothier, Lindsay, Prina, Carolyn, Morgan, Todd, Jamil, Arish, Heintzman, Sarah, Jockel-Balsarotti, Jennifer, Karanja, Elizabeth, Markway, Jesse, McCallum, Molly, Joslin, Ben, Alibazoglu, Deniz, Kolb, Stephen, Ajroud-Driss, Senda, Baloh, Robert, Heitzman, Daragh, Miller, Tim, Glass, Jonathan D, Patel-Murray, Natasha Leanna, Yu, Hong, Sinani, Ervin, Vigneswaran, Prasha, Sherman, Alexander V, Ahmad, Omar, Roy, Promit, Beavers, Jay C, Zeiler, Steven, Krakauer, John W, Agurto, Carla, Cecchi, Guillermo, Bellard, Mary, Raghav, Yogindra, Sachs, Karen, Ehrenberger, Tobias, Bruce, Elizabeth, Cudkowicz, Merit E, Maragakis, Nicholas, Norel, Raquel, Van Eyk, Jennifer E, Finkbeiner, Steven, Berry, James, Sareen, Dhruv, Thompson, Leslie M, Fraenkel, Ernest, and Svendsen, Clive N
Abstract: Answer ALS is a biological and clinical resource of patient-derived, induced pluripotent stem (iPS) cell lines, multi-omic data derived from iPS neurons and longitudinal clinical and smartphone data from over 1,000 patients with ALS. This resource provides population-level biological and clinical data that may be employed to identify clinical-molecular-biochemical subtypes of amyotrophic lateral sclerosis (ALS). A unique smartphone-based system was employed to collect deep clinical data, including fine motor activity, speech, breathing and linguistics/cognition. The iPS spinal neurons were blood derived from each patient and these cells underwent multi-omic analytics including whole-genome sequencing, RNA transcriptomics, ATAC-sequencing and proteomics. The intent of these data is for the generation of integrated clinical and biological signatures using bioinformatics, statistics and computational biology to establish patterns that may lead to a better understanding of the underlying mechanisms of disease, including subgroup identification. A web portal for open-source sharing of all data was developed for widespread community-based data analytics.
Published: 2022

4. Antiviral drug screen identifies DNA-damage response inhibitor as potent blocker of SARS-CoV-2 replication.

Author: Garcia, Gustavo, Garcia, Gustavo, Sharma, Arun, Ramaiah, Arunachalam, Sen, Chandani, Purkayastha, Arunima, Kohn, Donald B, Parcells, Mark S, Beck, Sebastian, Kim, Heeyoung, Bakowski, Malina A, Kirkpatrick, Melanie G, Riva, Laura, Wolff, Karen C, Han, Brandon, Yuen, Constance, Ulmert, David, Purbey, Prabhat K, Scumpia, Phillip, Beutler, Nathan, Rogers, Thomas F, Chatterjee, Arnab K, Gabriel, Gülsah, Bartenschlager, Ralf, Gomperts, Brigitte, Svendsen, Clive N, Betz, Ulrich AK, Damoiseaux, Robert D, Arumugaswami, Vaithilingaraja, Garcia, Gustavo, Garcia, Gustavo, Sharma, Arun, Ramaiah, Arunachalam, Sen, Chandani, Purkayastha, Arunima, Kohn, Donald B, Parcells, Mark S, Beck, Sebastian, Kim, Heeyoung, Bakowski, Malina A, Kirkpatrick, Melanie G, Riva, Laura, Wolff, Karen C, Han, Brandon, Yuen, Constance, Ulmert, David, Purbey, Prabhat K, Scumpia, Phillip, Beutler, Nathan, Rogers, Thomas F, Chatterjee, Arnab K, Gabriel, Gülsah, Bartenschlager, Ralf, Gomperts, Brigitte, Svendsen, Clive N, Betz, Ulrich AK, Damoiseaux, Robert D, and Arumugaswami, Vaithilingaraja
Abstract: SARS-CoV-2 has currently precipitated the COVID-19 global health crisis. We developed a medium-throughput drug-screening system and identified a small-molecule library of 34 of 430 protein kinase inhibitors that were capable of inhibiting the SARS-CoV-2 cytopathic effect in human epithelial cells. These drug inhibitors are in various stages of clinical trials. We detected key proteins involved in cellular signaling pathways mTOR-PI3K-AKT, ABL-BCR/MAPK, and DNA-damage response that are critical for SARS-CoV-2 infection. A drug-protein interaction-based secondary screen confirmed compounds, such as the ATR kinase inhibitor berzosertib and torin2 with anti-SARS-CoV-2 activity. Berzosertib exhibited potent antiviral activity against SARS-CoV-2 in multiple cell types and blocked replication at the post-entry step. Berzosertib inhibited replication of SARS-CoV-1 and the Middle East respiratory syndrome coronavirus (MERS-CoV) as well. Our study highlights key promising kinase inhibitors to constrain coronavirus replication as a host-directed therapy in the treatment of COVID-19 and beyond as well as provides an important mechanism of host-pathogen interactions.
Published: 2021

5. An integrated multi-omic analysis of iPSC-derived motor neurons from C9ORF72 ALS patients.

Author: NeuroLINCS Consortium, NeuroLINCS Consortium, Li, Jonathan, Lim, Ryan G, Kaye, Julia A, Dardov, Victoria, Coyne, Alyssa N, Wu, Jie, Milani, Pamela, Cheng, Andrew, Thompson, Terri G, Ornelas, Loren, Frank, Aaron, Adam, Miriam, Banuelos, Maria G, Casale, Malcolm, Cox, Veerle, Escalante-Chong, Renan, Daigle, J Gavin, Gomez, Emilda, Hayes, Lindsey, Holewenski, Ronald, Lei, Susan, Lenail, Alex, Lima, Leandro, Mandefro, Berhan, Matlock, Andrea, Panther, Lindsay, Patel-Murray, Natasha Leanna, Pham, Jacqueline, Ramamoorthy, Divya, Sachs, Karen, Shelley, Brandon, Stocksdale, Jennifer, Trost, Hannah, Wilhelm, Mark, Venkatraman, Vidya, Wassie, Brook T, Wyman, Stacia, Yang, Stephanie, NYGC ALS Consortium, Van Eyk, Jennifer E, Lloyd, Thomas E, Finkbeiner, Steven, Fraenkel, Ernest, Rothstein, Jeffrey D, Sareen, Dhruv, Svendsen, Clive N, Thompson, Leslie M, NeuroLINCS Consortium, NeuroLINCS Consortium, Li, Jonathan, Lim, Ryan G, Kaye, Julia A, Dardov, Victoria, Coyne, Alyssa N, Wu, Jie, Milani, Pamela, Cheng, Andrew, Thompson, Terri G, Ornelas, Loren, Frank, Aaron, Adam, Miriam, Banuelos, Maria G, Casale, Malcolm, Cox, Veerle, Escalante-Chong, Renan, Daigle, J Gavin, Gomez, Emilda, Hayes, Lindsey, Holewenski, Ronald, Lei, Susan, Lenail, Alex, Lima, Leandro, Mandefro, Berhan, Matlock, Andrea, Panther, Lindsay, Patel-Murray, Natasha Leanna, Pham, Jacqueline, Ramamoorthy, Divya, Sachs, Karen, Shelley, Brandon, Stocksdale, Jennifer, Trost, Hannah, Wilhelm, Mark, Venkatraman, Vidya, Wassie, Brook T, Wyman, Stacia, Yang, Stephanie, NYGC ALS Consortium, Van Eyk, Jennifer E, Lloyd, Thomas E, Finkbeiner, Steven, Fraenkel, Ernest, Rothstein, Jeffrey D, Sareen, Dhruv, Svendsen, Clive N, and Thompson, Leslie M
Abstract: Neurodegenerative diseases are challenging for systems biology because of the lack of reliable animal models or patient samples at early disease stages. Induced pluripotent stem cells (iPSCs) could address these challenges. We investigated DNA, RNA, epigenetics, and proteins in iPSC-derived motor neurons from patients with ALS carrying hexanucleotide expansions in C9ORF72. Using integrative computational methods combining all omics datasets, we identified novel and known dysregulated pathways. We used a C9ORF72 Drosophila model to distinguish pathways contributing to disease phenotypes from compensatory ones and confirmed alterations in some pathways in postmortem spinal cord tissue of patients with ALS. A different differentiation protocol was used to derive a separate set of C9ORF72 and control motor neurons. Many individual -omics differed by protocol, but some core dysregulated pathways were consistent. This strategy of analyzing patient-specific neurons provides disease-related outcomes with small numbers of heterogeneous lines and reduces variation from single-omics to elucidate network-based signatures.
Published: 2021

6. Human iPSC-derived fallopian tube organoids with BRCA1 mutation recapitulate early-stage carcinogenesis.

Author: Yucer, Nur, Yucer, Nur, Ahdoot, Rodney, Workman, Michael J, Laperle, Alexander H, Recouvreux, Maria S, Kurowski, Kathleen, Naboulsi, Diana J, Liang, Victoria, Qu, Ying, Plummer, Jasmine T, Gayther, Simon A, Orsulic, Sandra, Karlan, Beth Y, Svendsen, Clive N, Yucer, Nur, Yucer, Nur, Ahdoot, Rodney, Workman, Michael J, Laperle, Alexander H, Recouvreux, Maria S, Kurowski, Kathleen, Naboulsi, Diana J, Liang, Victoria, Qu, Ying, Plummer, Jasmine T, Gayther, Simon A, Orsulic, Sandra, Karlan, Beth Y, and Svendsen, Clive N
Abstract: Germline pathogenic mutations in BReast CAncer (BRCA1) genes are thought to drive normal fallopian tube epithelial (FTE) cell transformation to high-grade serous ovarian cancer. No human models capture the sequence of events for disease initiation and progression. Here, we generate induced pluripotent stem cells (iPSCs) from healthy individuals and young ovarian cancer patients with germline pathogenic BRCA1 mutations (BRCA1mut). Following differentiation into FTE organoids, BRCA1mut lines exhibit cellular abnormalities consistent with neoplastic transformation compared to controls. BRCA1mut organoids show an increased production of cancer-specific proteins and survival following transplantation into mice. Organoids from women with the most aggressive ovarian cancer show the greatest pathology, indicating the potential value to predict clinical severity prior to disease onset. These human FTE organoids from BRCA1mut carriers provide a faithful physiological in vitro model of FTE lesion generation and early carcinogenesis. This platform can be used for personalized mechanistic and drug screening studies.
Published: 2021

7. Antiviral drug screen identifies DNA-damage response inhibitor as potent blocker of SARS-CoV-2 replication.

Author: Garcia, Gustavo, Garcia, Gustavo, Sharma, Arun, Ramaiah, Arunachalam, Sen, Chandani, Purkayastha, Arunima, Kohn, Donald B, Parcells, Mark S, Beck, Sebastian, Kim, Heeyoung, Bakowski, Malina A, Kirkpatrick, Melanie G, Riva, Laura, Wolff, Karen C, Han, Brandon, Yuen, Constance, Ulmert, David, Purbey, Prabhat K, Scumpia, Philip, Beutler, Nathan, Rogers, Thomas F, Chatterjee, Arnab K, Gabriel, Gülsah, Bartenschlager, Ralf, Gomperts, Brigitte, Svendsen, Clive N, Betz, Ulrich AK, Damoiseaux, Robert D, Arumugaswami, Vaithilingaraja, Garcia, Gustavo, Garcia, Gustavo, Sharma, Arun, Ramaiah, Arunachalam, Sen, Chandani, Purkayastha, Arunima, Kohn, Donald B, Parcells, Mark S, Beck, Sebastian, Kim, Heeyoung, Bakowski, Malina A, Kirkpatrick, Melanie G, Riva, Laura, Wolff, Karen C, Han, Brandon, Yuen, Constance, Ulmert, David, Purbey, Prabhat K, Scumpia, Philip, Beutler, Nathan, Rogers, Thomas F, Chatterjee, Arnab K, Gabriel, Gülsah, Bartenschlager, Ralf, Gomperts, Brigitte, Svendsen, Clive N, Betz, Ulrich AK, Damoiseaux, Robert D, and Arumugaswami, Vaithilingaraja
Abstract: SARS-CoV-2 has currently precipitated the COVID-19 global health crisis. We developed a medium-throughput drug-screening system and identified a small-molecule library of 34 of 430 protein kinase inhibitors that were capable of inhibiting the SARS-CoV-2 cytopathic effect in human epithelial cells. These drug inhibitors are in various stages of clinical trials. We detected key proteins involved in cellular signaling pathways mTOR-PI3K-AKT, ABL-BCR/MAPK, and DNA-damage response that are critical for SARS-CoV-2 infection. A drug-protein interaction-based secondary screen confirmed compounds, such as the ATR kinase inhibitor berzosertib and torin2 with anti-SARS-CoV-2 activity. Berzosertib exhibited potent antiviral activity against SARS-CoV-2 in multiple cell types and blocked replication at the post-entry step. Berzosertib inhibited replication of SARS-CoV-1 and the Middle East respiratory syndrome coronavirus (MERS-CoV) as well. Our study highlights key promising kinase inhibitors to constrain coronavirus replication as a host-directed therapy in the treatment of COVID-19 and beyond as well as provides an important mechanism of host-pathogen interactions.
Published: 2021

8. An integrated multi-omic analysis of iPSC-derived motor neurons from C9ORF72 ALS patients.

Author: NeuroLINCS Consortium, NeuroLINCS Consortium, Li, Jonathan, Lim, Ryan G, Kaye, Julia A, Dardov, Victoria, Coyne, Alyssa N, Wu, Jie, Milani, Pamela, Cheng, Andrew, Thompson, Terri G, Ornelas, Loren, Frank, Aaron, Adam, Miriam, Banuelos, Maria G, Casale, Malcolm, Cox, Veerle, Escalante-Chong, Renan, Daigle, J Gavin, Gomez, Emilda, Hayes, Lindsey, Holewenski, Ronald, Lei, Susan, Lenail, Alex, Lima, Leandro, Mandefro, Berhan, Matlock, Andrea, Panther, Lindsay, Patel-Murray, Natasha Leanna, Pham, Jacqueline, Ramamoorthy, Divya, Sachs, Karen, Shelley, Brandon, Stocksdale, Jennifer, Trost, Hannah, Wilhelm, Mark, Venkatraman, Vidya, Wassie, Brook T, Wyman, Stacia, Yang, Stephanie, NYGC ALS Consortium, Van Eyk, Jennifer E, Lloyd, Thomas E, Finkbeiner, Steven, Fraenkel, Ernest, Rothstein, Jeffrey D, Sareen, Dhruv, Svendsen, Clive N, Thompson, Leslie M, NeuroLINCS Consortium, NeuroLINCS Consortium, Li, Jonathan, Lim, Ryan G, Kaye, Julia A, Dardov, Victoria, Coyne, Alyssa N, Wu, Jie, Milani, Pamela, Cheng, Andrew, Thompson, Terri G, Ornelas, Loren, Frank, Aaron, Adam, Miriam, Banuelos, Maria G, Casale, Malcolm, Cox, Veerle, Escalante-Chong, Renan, Daigle, J Gavin, Gomez, Emilda, Hayes, Lindsey, Holewenski, Ronald, Lei, Susan, Lenail, Alex, Lima, Leandro, Mandefro, Berhan, Matlock, Andrea, Panther, Lindsay, Patel-Murray, Natasha Leanna, Pham, Jacqueline, Ramamoorthy, Divya, Sachs, Karen, Shelley, Brandon, Stocksdale, Jennifer, Trost, Hannah, Wilhelm, Mark, Venkatraman, Vidya, Wassie, Brook T, Wyman, Stacia, Yang, Stephanie, NYGC ALS Consortium, Van Eyk, Jennifer E, Lloyd, Thomas E, Finkbeiner, Steven, Fraenkel, Ernest, Rothstein, Jeffrey D, Sareen, Dhruv, Svendsen, Clive N, and Thompson, Leslie M
Abstract: Neurodegenerative diseases are challenging for systems biology because of the lack of reliable animal models or patient samples at early disease stages. Induced pluripotent stem cells (iPSCs) could address these challenges. We investigated DNA, RNA, epigenetics, and proteins in iPSC-derived motor neurons from patients with ALS carrying hexanucleotide expansions in C9ORF72. Using integrative computational methods combining all omics datasets, we identified novel and known dysregulated pathways. We used a C9ORF72 Drosophila model to distinguish pathways contributing to disease phenotypes from compensatory ones and confirmed alterations in some pathways in postmortem spinal cord tissue of patients with ALS. A different differentiation protocol was used to derive a separate set of C9ORF72 and control motor neurons. Many individual -omics differed by protocol, but some core dysregulated pathways were consistent. This strategy of analyzing patient-specific neurons provides disease-related outcomes with small numbers of heterogeneous lines and reduces variation from single-omics to elucidate network-based signatures.
Published: 2021

9. Human iPSC-derived fallopian tube organoids with BRCA1 mutation recapitulate early-stage carcinogenesis.

Author: Yucer, Nur, Yucer, Nur, Ahdoot, Rodney, Workman, Michael J, Laperle, Alexander H, Recouvreux, Maria S, Kurowski, Kathleen, Naboulsi, Diana J, Liang, Victoria, Qu, Ying, Plummer, Jasmine T, Gayther, Simon A, Orsulic, Sandra, Karlan, Beth Y, Svendsen, Clive N, Yucer, Nur, Yucer, Nur, Ahdoot, Rodney, Workman, Michael J, Laperle, Alexander H, Recouvreux, Maria S, Kurowski, Kathleen, Naboulsi, Diana J, Liang, Victoria, Qu, Ying, Plummer, Jasmine T, Gayther, Simon A, Orsulic, Sandra, Karlan, Beth Y, and Svendsen, Clive N
Abstract: Germline pathogenic mutations in BReast CAncer (BRCA1) genes are thought to drive normal fallopian tube epithelial (FTE) cell transformation to high-grade serous ovarian cancer. No human models capture the sequence of events for disease initiation and progression. Here, we generate induced pluripotent stem cells (iPSCs) from healthy individuals and young ovarian cancer patients with germline pathogenic BRCA1 mutations (BRCA1mut). Following differentiation into FTE organoids, BRCA1mut lines exhibit cellular abnormalities consistent with neoplastic transformation compared to controls. BRCA1mut organoids show an increased production of cancer-specific proteins and survival following transplantation into mice. Organoids from women with the most aggressive ovarian cancer show the greatest pathology, indicating the potential value to predict clinical severity prior to disease onset. These human FTE organoids from BRCA1mut carriers provide a faithful physiological in vitro model of FTE lesion generation and early carcinogenesis. This platform can be used for personalized mechanistic and drug screening studies.
Published: 2021

10. Cross-Comparison of Human iPSC Motor Neuron Models of Familial and Sporadic ALS Reveals Early and Convergent Transcriptomic Disease Signatures.

Author: Ho, Ritchie, Ho, Ritchie, Workman, Michael J, Mathkar, Pranav, Wu, Kathryn, Kim, Kevin J, O'Rourke, Jacqueline G, Kellogg, Mariko, Montel, Valerie, Banuelos, Maria G, Arogundade, Olubankole Aladesuyi, Diaz-Garcia, Sandra, Oheb, Daniel, Huang, Steven, Khrebtukova, Irina, Watson, Lisa, Ravits, John, Taylor, Kevin, Baloh, Robert H, Svendsen, Clive N, Ho, Ritchie, Ho, Ritchie, Workman, Michael J, Mathkar, Pranav, Wu, Kathryn, Kim, Kevin J, O'Rourke, Jacqueline G, Kellogg, Mariko, Montel, Valerie, Banuelos, Maria G, Arogundade, Olubankole Aladesuyi, Diaz-Garcia, Sandra, Oheb, Daniel, Huang, Steven, Khrebtukova, Irina, Watson, Lisa, Ravits, John, Taylor, Kevin, Baloh, Robert H, and Svendsen, Clive N
Abstract: Induced pluripotent stem cell (iPSC)-derived neural cultures from amyotrophic lateral sclerosis (ALS) patients can model disease phenotypes. However, heterogeneity arising from genetic and experimental variability limits their utility, impacting reproducibility and the ability to track cellular origins of pathogenesis. Here, we present methodologies using single-cell RNA sequencing (scRNA-seq) analysis to address these limitations. By repeatedly differentiating and applying scRNA-seq to motor neurons (MNs) from healthy, familial ALS, sporadic ALS, and genome-edited iPSC lines across multiple patients, batches, and platforms, we account for genetic and experimental variability toward identifying unified and reproducible ALS signatures. Combining HOX and developmental gene expression with global clustering, we anatomically classified cells into rostrocaudal, progenitor, and postmitotic identities. By relaxing statistical thresholds, we discovered genes in iPSC-MNs that were concordantly dysregulated in postmortem MNs and yielded predictive ALS markers in other human and mouse models. Our approach thus revealed early, convergent, and MN-resolved signatures of ALS.
Published: 2021

11. Generation of a Human iPSC-Based Blood-Brain Barrier Chip

Author: Jagadeesan, Srikanth, Workman, Michael J., Herland, Anna, Svendsen, Clive N., Vatine, Gad D., Jagadeesan, Srikanth, Workman, Michael J., Herland, Anna, Svendsen, Clive N., and Vatine, Gad D.
Abstract: The blood brain barrier (BBB) is formed by neurovascular units (NVUs) that shield the central nervous system (CNS) from a range of factors found in the blood that can disrupt delicate brain function. As such, the BBB is a major obstacle to the delivery of therapeutics to the CNS. Accumulating evidence suggests that the BBB plays a key role in the onset and progression of neurological diseases. Thus, there is a tremendous need for a BBB model that can predict penetration of CNS-targeted drugs as well as elucidate the BBB's role in health and disease. We have recently combined organ-on-chip and induced pluripotent stem cell (iPSC) technologies to generate a BBB chip fully personalized to humans. This novel platform displays cellular, molecular, and physiological properties that are suitable for the prediction of drug and molecule transport across the human BBB. Furthermore, using patient-specific BBB chips, we have generated models of neurological disease and demonstrated the potential for personalized predictive medicine applications. Provided here is a detailed protocol demonstrating how to generate iPSC-derived BBB chips, beginning with differentiation of iPSC-derived brain microvascular endothelial cells (iBMECs) and resulting in mixed neural cultures containing neural progenitors, differentiated neurons, and astrocytes. Also described is a procedure for seeding cells into the organ chip and culturing of the BBB chips under controlled laminar flow. Lastly, detailed descriptions of BBB chip analyses are provided, including paracellular permeability assays for assessing drug and molecule permeability as well as immunocytochemical methods for determining the composition of cell types within the chip., QC 20200512
Published: 2020
Full Text: View/download PDF

12. Human iPSC-Derived Cardiomyocytes Are Susceptible to SARS-CoV-2 Infection.

Author: Sharma, Arun, Sharma, Arun, Garcia, Gustavo, Wang, Yizhou, Plummer, Jasmine T, Morizono, Kouki, Arumugaswami, Vaithilingaraja, Svendsen, Clive N, Sharma, Arun, Sharma, Arun, Garcia, Gustavo, Wang, Yizhou, Plummer, Jasmine T, Morizono, Kouki, Arumugaswami, Vaithilingaraja, and Svendsen, Clive N
Abstract: Coronavirus disease 2019 (COVID-19) is a pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 is defined by respiratory symptoms, but cardiac complications including viral myocarditis are also prevalent. Although ischemic and inflammatory responses caused by COVID-19 can detrimentally affect cardiac function, the direct impact of SARS-CoV-2 infection on human cardiomyocytes is not well understood. Here, we utilize human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) as a model to examine the mechanisms of cardiomyocyte-specific infection by SARS-CoV-2. Microscopy and RNA sequencing demonstrate that SARS-CoV-2 can enter hiPSC-CMs via ACE2. Viral replication and cytopathic effect induce hiPSC-CM apoptosis and cessation of beating after 72 h of infection. SARS-CoV-2 infection activates innate immune response and antiviral clearance gene pathways, while inhibiting metabolic pathways and suppressing ACE2 expression. These studies show that SARS-CoV-2 can infect hiPSC-CMs in vitro, establishing a model for elucidating infection mechanisms and potentially a cardiac-specific antiviral drug screening platform.
Published: 2020

13. G4C2 Repeat RNA Initiates a POM121-Mediated Reduction in Specific Nucleoporins in C9orf72 ALS/FTD.

Author: Coyne, Alyssa N, Coyne, Alyssa N, Zaepfel, Benjamin L, Hayes, Lindsey, Fitchman, Boris, Salzberg, Yuval, Luo, En-Ching, Bowen, Kelly, Trost, Hannah, Aigner, Stefan, Rigo, Frank, Yeo, Gene W, Harel, Amnon, Svendsen, Clive N, Sareen, Dhruv, Rothstein, Jeffrey D, Coyne, Alyssa N, Coyne, Alyssa N, Zaepfel, Benjamin L, Hayes, Lindsey, Fitchman, Boris, Salzberg, Yuval, Luo, En-Ching, Bowen, Kelly, Trost, Hannah, Aigner, Stefan, Rigo, Frank, Yeo, Gene W, Harel, Amnon, Svendsen, Clive N, Sareen, Dhruv, and Rothstein, Jeffrey D
Abstract: Through mechanisms that remain poorly defined, defects in nucleocytoplasmic transport and accumulations of specific nuclear-pore-complex-associated proteins have been reported in multiple neurodegenerative diseases, including C9orf72 Amyotrophic Lateral Sclerosis and Frontotemporal Dementia (ALS/FTD). Using super-resolution structured illumination microscopy, we have explored the mechanism by which nucleoporins are altered in nuclei isolated from C9orf72 induced pluripotent stem-cell-derived neurons (iPSNs). Of the 23 nucleoporins evaluated, we observed a reduction in a subset of 8, including key components of the nuclear pore complex scaffold and the transmembrane nucleoporin POM121. Reduction in POM121 appears to initiate a decrease in the expression of seven additional nucleoporins, ultimately affecting the localization of Ran GTPase and subsequent cellular toxicity in C9orf72 iPSNs. Collectively, our data suggest that the expression of expanded C9orf72 ALS/FTD repeat RNA alone affects nuclear POM121 expression in the initiation of a pathological cascade affecting nucleoporin levels within neuronal nuclei and ultimately downstream neuronal survival.
Published: 2020

14. In Vitro and In Vivo Proteomic Comparison of Human Neural Progenitor Cell-Induced Photoreceptor Survival.

Author: Jones, Melissa K, Jones, Melissa K, Lu, Bin, Chen, Dawn Zhaohui, Spivia, Weston R, Mercado, Augustus T, Ljubimov, Alexander V, Svendsen, Clive N, Van Eyk, Jennifer E, Wang, Shaomei, Jones, Melissa K, Jones, Melissa K, Lu, Bin, Chen, Dawn Zhaohui, Spivia, Weston R, Mercado, Augustus T, Ljubimov, Alexander V, Svendsen, Clive N, Van Eyk, Jennifer E, and Wang, Shaomei
Abstract: Retinal degenerative diseases lead to blindness with few treatments. Various cell-based therapies are aimed to slow the progression of vision loss by preserving light-sensing photoreceptor cells. A subretinal injection of human neural progenitor cells (hNPCs) into the Royal College of Surgeons (RCS) rat model of retinal degeneration has aided in photoreceptor survival, though the mechanisms are mainly unknown. Identifying the retinal proteomic changes that occur following hNPC treatment leads to better understanding of neuroprotection. To mimic the retinal environment following hNPC injection, a co-culture system of retinas and hNPCs is developed. Less cell death occurs in RCS retinal tissue co-cultured with hNPCs than in retinas cultured alone, suggesting that hNPCs provide retinal protection in vitro. Comparison of ex vivo and in vivo retinas identifies nuclear factor (erythroid-derived 2)-like 2 (NRF2) mediated oxidative response signaling as an hNPC-induced pathway. This is the first study to compare proteomic changes following treatment with hNPCs in both an ex vivo and in vivo environment, further allowing the use of ex vivo modeling for mechanisms of retinal preservation. Elucidation of the protein changes in the retina following hNPC treatment may lead to the discovery of mechanisms of photoreceptor survival and its therapeutic for clinical applications.
Published: 2019

15. Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

Author: Nicolas, Aude, Kenna, Kevin P., Renton, Alan E., Ticozzi, Nicola, Faghri, Faraz, Chia, Ruth, Dominov, Janice A., Kenna, Brendan J., Nalls, Mike A., Keagle, Pamela, Rivera, Alberto M., van Rheenen, Wouter, Murphy, Natalie A., van Vugt, Joke J. F. A., Geiger, Joshua T., van der Spek, Rick A., Pliner, Hannah A., Shankaracharya, Smith, Bradley N., Marangi, Giuseppe, Topp, Simon D., Abramzon, Yevgeniya, Gkazi, Athina Soragia, Eicher, John D., Kenna, Aoife, Mora, Gabriele, Calvo, Andrea, Mazzini, Letizia, Riva, Nilo, Mandrioli, Jessica, Caponnetto, Claudia, Battistini, Stefania, Volanti, Paolo, La Bella, Vincenzo, Conforti, Francesca L., Borghero, Giuseppe, Messina, Sonia, Simone, Isabella L., Trojsi, Francesca, Salvi, Fabrizio, Logullo, Francesco O., D'Alfonso, Sandra, Corrado, Lucia, Capasso, Margherita, Ferrucci, Luigi, Moreno, Cristiane de Araujo Martins, Kamalakaran, Sitharthan, Goldstein, David B., Gitler, Aaron D., Harris, Tim, Myers, Richard M., Phatnani, Hemali, Musunuri, Rajeeva Lochan, Evani, Uday Shankar, Abhyankar, Avinash, Zody, Michael C., Kaye, Julia, Finkbeiner, Steven, Wyman, Stacia K., LeNail, Alex, Lima, Leandro, Fraenkel, Ernest, Svendsen, Clive N., Thompson, Leslie M., Van Eyk, Jennifer E., Berry, James D., Miller, Timothy M., Kolb, Stephen J., Cudkowicz, Merit, Baxi, Emily, Benatar, Michael, Taylor, J. Paul, Rampersaud, Evadnie, Wu, Gang, Wuu, Joanne, Lauria, Giuseppe, Verde, Federico, Fogh, Isabella, Tiloca, Cinzia, Comi, Giacomo P., Soraru, Gianni, Cereda, Cristina, Corcia, Philippe, Laaksovirta, Hannu, Myllykangas, Liisa, Jansson, Lilja, Valori, Miko, Ealing, John, Hamdalla, Hisham, Rollinson, Sara, Pickering-Brown, Stuart, Orrell, Richard W., Sidle, Katie C., Malaspina, Andrea, Hardy, John, Singleton, Andrew B., Johnson, Janel O., Arepalli, Sampath, Sapp, Peter C., McKenna-Yasek, Diane, Polak, Meraida, Asress, Seneshaw, Al-Sarraj, Safa, King, Andrew, Troakes, Claire, Vance, Caroline, de Belleroche, Jacqueline, Baas, Frank, ten Asbroek, Anneloor L. M. A., Luis Munoz-Blanco, Jose, Hernandez, Dena G., Ding, Jinhui, Gibbs, J. Raphael, Scholz, Sonja W., Floeter, Mary Kay, Campbell, Roy H., Landi, Francesco, Bowser, Robert, Pulst, Stefan M., Ravits, John M., MacGowan, Daniel J. L., Kirby, Janine, Pioro, Erik P., Pamphlett, Roger, Broach, James, Gerhard, Glenn, Dunckley, Travis L., Brady, Christopher B., Kowall, Neil W., Troncoso, Juan C., Le Ber, Isabelle, Mouzat, Kevin, Lumbroso, Serge, Heiman-Patterson, Terry D., Kamel, Freya, Van Den Bosch, Ludo, Baloh, Robert H., Strom, Tim M., Meitinger, Thomas, Shatunov, Aleksey, Van Eijk, Kristel R., de Carvalho, Mamede, Kooyman, Maarten, Middelkoop, Bas, Moisse, Matthieu, McLaughlin, Russell L., Van Es, Michael A., Weber, Markus, Boylan, Kevin B., Van Blitterswijk, Marka, Rademakers, Rosa, Morrison, Karen E., Basak, A. Nazli, Mora, Jesus S., Drory, Vivian E., Shaw, Pamela J., Turner, Martin R., Talbot, Kevin, Hardiman, Orla, Williams, Kelly L., Fifita, Jennifer A., Nicholson, Garth A., Blair, Ian P., Rouleau, Guy A., Esteban-Perez, Jesus, Garcia-Redondo, Alberto, Al-Chalabi, Ammar, Rogaeva, Ekaterina, Zinman, Lorne, Ostrow, Lyle W., Maragakis, Nicholas J., Rothstein, Jeffrey D., Simmons, Zachary, Cooper-Knock, Johnathan, Brice, Alexis, Goutman, Stephen A., Feldman, Eva L., Gibson, Summer B., Taroni, Franco, Ratti, Antonia, Gellera, Cinzia, Van Damme, Philip, Robberecht, Wim, Fratta, Pietro, Sabatelli, Mario, Lunetta, Christian, Ludolph, Albert C., Andersen, Peter M., Weishaupt, Jochen H., Camu, William, Trojanowski, John Q., Van Deerlin, Vivianna M., Brown, Robert H., Jr., van den Berg, Leonard H., Veldink, Jan H., Harms, Matthew B., Glass, Jonathan D., Stone, David J., Tienari, Pentti, Silani, Vincenzo, Chio, Adriano, Shaw, Christopher E., Traynor, Bryan J., Landers, John E., Nicolas, Aude, Kenna, Kevin P., Renton, Alan E., Ticozzi, Nicola, Faghri, Faraz, Chia, Ruth, Dominov, Janice A., Kenna, Brendan J., Nalls, Mike A., Keagle, Pamela, Rivera, Alberto M., van Rheenen, Wouter, Murphy, Natalie A., van Vugt, Joke J. F. A., Geiger, Joshua T., van der Spek, Rick A., Pliner, Hannah A., Shankaracharya, Smith, Bradley N., Marangi, Giuseppe, Topp, Simon D., Abramzon, Yevgeniya, Gkazi, Athina Soragia, Eicher, John D., Kenna, Aoife, Mora, Gabriele, Calvo, Andrea, Mazzini, Letizia, Riva, Nilo, Mandrioli, Jessica, Caponnetto, Claudia, Battistini, Stefania, Volanti, Paolo, La Bella, Vincenzo, Conforti, Francesca L., Borghero, Giuseppe, Messina, Sonia, Simone, Isabella L., Trojsi, Francesca, Salvi, Fabrizio, Logullo, Francesco O., D'Alfonso, Sandra, Corrado, Lucia, Capasso, Margherita, Ferrucci, Luigi, Moreno, Cristiane de Araujo Martins, Kamalakaran, Sitharthan, Goldstein, David B., Gitler, Aaron D., Harris, Tim, Myers, Richard M., Phatnani, Hemali, Musunuri, Rajeeva Lochan, Evani, Uday Shankar, Abhyankar, Avinash, Zody, Michael C., Kaye, Julia, Finkbeiner, Steven, Wyman, Stacia K., LeNail, Alex, Lima, Leandro, Fraenkel, Ernest, Svendsen, Clive N., Thompson, Leslie M., Van Eyk, Jennifer E., Berry, James D., Miller, Timothy M., Kolb, Stephen J., Cudkowicz, Merit, Baxi, Emily, Benatar, Michael, Taylor, J. Paul, Rampersaud, Evadnie, Wu, Gang, Wuu, Joanne, Lauria, Giuseppe, Verde, Federico, Fogh, Isabella, Tiloca, Cinzia, Comi, Giacomo P., Soraru, Gianni, Cereda, Cristina, Corcia, Philippe, Laaksovirta, Hannu, Myllykangas, Liisa, Jansson, Lilja, Valori, Miko, Ealing, John, Hamdalla, Hisham, Rollinson, Sara, Pickering-Brown, Stuart, Orrell, Richard W., Sidle, Katie C., Malaspina, Andrea, Hardy, John, Singleton, Andrew B., Johnson, Janel O., Arepalli, Sampath, Sapp, Peter C., McKenna-Yasek, Diane, Polak, Meraida, Asress, Seneshaw, Al-Sarraj, Safa, King, Andrew, Troakes, Claire, Vance, Caroline, de Belleroche, Jacqueline, Baas, Frank, ten Asbroek, Anneloor L. M. A., Luis Munoz-Blanco, Jose, Hernandez, Dena G., Ding, Jinhui, Gibbs, J. Raphael, Scholz, Sonja W., Floeter, Mary Kay, Campbell, Roy H., Landi, Francesco, Bowser, Robert, Pulst, Stefan M., Ravits, John M., MacGowan, Daniel J. L., Kirby, Janine, Pioro, Erik P., Pamphlett, Roger, Broach, James, Gerhard, Glenn, Dunckley, Travis L., Brady, Christopher B., Kowall, Neil W., Troncoso, Juan C., Le Ber, Isabelle, Mouzat, Kevin, Lumbroso, Serge, Heiman-Patterson, Terry D., Kamel, Freya, Van Den Bosch, Ludo, Baloh, Robert H., Strom, Tim M., Meitinger, Thomas, Shatunov, Aleksey, Van Eijk, Kristel R., de Carvalho, Mamede, Kooyman, Maarten, Middelkoop, Bas, Moisse, Matthieu, McLaughlin, Russell L., Van Es, Michael A., Weber, Markus, Boylan, Kevin B., Van Blitterswijk, Marka, Rademakers, Rosa, Morrison, Karen E., Basak, A. Nazli, Mora, Jesus S., Drory, Vivian E., Shaw, Pamela J., Turner, Martin R., Talbot, Kevin, Hardiman, Orla, Williams, Kelly L., Fifita, Jennifer A., Nicholson, Garth A., Blair, Ian P., Rouleau, Guy A., Esteban-Perez, Jesus, Garcia-Redondo, Alberto, Al-Chalabi, Ammar, Rogaeva, Ekaterina, Zinman, Lorne, Ostrow, Lyle W., Maragakis, Nicholas J., Rothstein, Jeffrey D., Simmons, Zachary, Cooper-Knock, Johnathan, Brice, Alexis, Goutman, Stephen A., Feldman, Eva L., Gibson, Summer B., Taroni, Franco, Ratti, Antonia, Gellera, Cinzia, Van Damme, Philip, Robberecht, Wim, Fratta, Pietro, Sabatelli, Mario, Lunetta, Christian, Ludolph, Albert C., Andersen, Peter M., Weishaupt, Jochen H., Camu, William, Trojanowski, John Q., Van Deerlin, Vivianna M., Brown, Robert H., Jr., van den Berg, Leonard H., Veldink, Jan H., Harms, Matthew B., Glass, Jonathan D., Stone, David J., Tienari, Pentti, Silani, Vincenzo, Chio, Adriano, Shaw, Christopher E., Traynor, Bryan J., and Landers, John E.
Abstract: To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.
Published: 2018
Full Text: View/download PDF

16. Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

Author: Nicolas, A, Kenna, K, Renton, A, Ticozzi, N, Faghri, F, Chia, R, Dominov, J, Kenna, B, Nalls, M, Keagle, P, Rivera, A, van Rheenen, W, Murphy, N, van Vugt, J, Geiger, J, van der Spek, R, Pliner, H, Shankaracharya, N, Smith, B, Marangi, G, Topp, S, Abramzon, Y, Gkazi, A, Eicher, J, Kenna, A, Logullo, F, Simone, I, Logroscino, G, Salvi, F, Bartolomei, I, Borghero, G, Murru, M, Costantino, E, Pani, C, Puddu, R, Caredda, C, Piras, V, Tranquilli, S, Cuccu, S, Corongiu, D, Melis, M, Milia, A, Marrosu, F, Marrosu, M, Floris, G, Cannas, A, Capasso, M, Caponnetto, C, Mancardi, G, Origone, P, Mandich, P, Conforti, F, Cavallaro, S, Mora, G, Marinou, K, Sideri, R, Penco, S, Mosca, L, Lunetta, C, Pinter, G, Corbo, M, Riva, N, Carrera, P, Volanti, P, Mandrioli, J, Fini, N, Fasano, A, Tremolizzo, L, Arosio, A, Ferrarese, C, Trojsi, F, Tedeschi, G, Monsurrò, M, Piccirillo, G, Femiano, C, Ticca, A, Ortu, E, La Bella, V, Spataro, R, Colletti, T, Sabatelli, M, Zollino, M, Conte, A, Luigetti, M, Lattante, S, Santarelli, M, Petrucci, A, Pugliatti, M, Pirisi, A, Parish, L, Occhineri, P, Giannini, F, Battistini, S, Ricci, C, Benigni, M, Cau, T, Loi, D, Calvo, A, Moglia, C, Brunetti, M, Barberis, M, Restagno, G, Casale, F, Marrali, G, Fuda, G, Ossola, I, Cammarosano, S, Canosa, A, Ilardi, A, Manera, U, Grassano, M, Tanel, R, Pisano, F, Mazzini, L, Messina, S, D'Alfonso, S, Corrado, L, Ferrucci, L, Harms, M, Goldstein, D, Shneider, N, Goutman, S, Simmons, Z, Miller, T, Chandran, S, Pal, S, Manousakis, G, Appel, S, Simpson, E, Wang, L, Baloh, R, Gibson, S, Bedlack, R, Lacomis, D, Sareen, D, Sherman, A, Bruijn, L, Penny, M, Moreno, C, Kamalakaran, S, Allen, A, Boone, B, Brown, R, Carulli, J, Chesi, A, Chung, W, Cirulli, E, Cooper, G, Couthouis, J, Day-Williams, A, Dion, P, Gitler, A, Glass, J, Han, Y, Harris, T, Hayes, S, Jones, A, Keebler, J, Krueger, B, Lasseigne, B, Levy, S, Lu, Y, Maniatis, T, McKenna-Yasek, D, Myers, R, Petrovski, S, Pulst, S, Raphael, A, Ravits, J, Ren, Z, Rouleau, G, Sapp, P, Sims, K, Staropoli, J, Waite, L, Wang, Q, Wimbish, J, Xin, W, Phatnani, H, Kwan, J, Broach, J, Arcila-Londono, X, Lee, E, Van Deerlin, V, Fraenkel, E, Ostrow, L, Baas, F, Zaitlen, N, Berry, J, Malaspina, A, Fratta, P, Cox, G, Thompson, L, Finkbeiner, S, Dardiotis, E, Hornstein, E, Macgowan, D, Heiman-Patterson, T, Hammell, M, Patsopoulos, N, Dubnau, J, Nath, A, Musunuri, R, Evani, U, Abhyankar, A, Zody, M, Kaye, J, Wyman, S, Lenail, A, Lima, L, Rothstein, J, Svendsen, C, Van Eyk, J, Maragakis, N, Kolb, S, Cudkowicz, M, Baxi, E, Benatar, M, Taylor, J, Wu, G, Rampersaud, E, Wuu, J, Rademakers, R, Züchner, S, Schule, R, Mccauley, J, Hussain, S, Cooley, A, Wallace, M, Clayman, C, Barohn, R, Statland, J, Swenson, A, Jackson, C, Trivedi, J, Khan, S, Katz, J, Jenkins, L, Burns, T, Gwathmey, K, Caress, J, Mcmillan, C, Elman, L, Pioro, E, Heckmann, J, So, Y, Walk, D, Maiser, S, Zhang, J, Silani, V, Gellera, C, Ratti, A, Taroni, F, Lauria, G, Verde, F, Fogh, I, Tiloca, C, Comi, G, Sorarù, G, Cereda, C, De Marchi, F, Corti, S, Ceroni, M, Siciliano, G, Filosto, M, Inghilleri, M, Peverelli, S, Colombrita, C, Poletti, B, Maderna, L, Del Bo, R, Gagliardi, S, Querin, G, Bertolin, C, Pensato, V, Castellotti, B, Camu, W, Mouzat, K, Lumbroso, S, Corcia, P, Meininger, V, Besson, G, Lagrange, E, Clavelou, P, Guy, N, Couratier, P, Vourch, P, Danel, V, Bernard, E, Lemasson, G, Laaksovirta, H, Myllykangas, L, Jansson, L, Valori, M, Ealing, J, Hamdalla, H, Rollinson, S, Pickering-Brown, S, Orrell, R, Sidle, K, Hardy, J, Singleton, A, Johnson, J, Arepalli, S, Polak, M, Asress, S, Al-Sarraj, S, King, A, Troakes, C, Vance, C, de Belleroche, J, ten Asbroek, A, Muñoz-Blanco, J, Hernandez, D, Ding, J, Gibbs, J, Scholz, S, Floeter, M, Campbell, R, Landi, F, Bowser, R, Kirby, J, Pamphlett, R, Gerhard, G, Dunckley, T, Brady, C, Kowall, N, Troncoso, J, Le Ber, I, Kamel, F, Van Den Bosch, L, Strom, T, Meitinger, T, Shatunov, A, Van Eijk, K, de Carvalho, M, Kooyman, M, Middelkoop, B, Moisse, M, Mclaughlin, R, Van Es, M, Weber, M, Boylan, K, Van Blitterswijk, M, Morrison, K, Basak, A, Mora, J, Drory, V, Shaw, P, Turner, M, Talbot, K, Hardiman, O, Williams, K, Fifita, J, Nicholson, G, Blair, I, Esteban-Pérez, J, García-Redondo, A, Al-Chalabi, A, Al Kheifat, A, Andersen, P, Chio, A, Cooper-Knock, J, Dekker, A, Redondo, A, Gotkine, M, Hide, W, Iacoangeli, A, Kiernan, M, Landers, J, Mill, J, Neto, M, Pardina, J, Newhouse, S, Pinto, S, Pulit, S, Robberecht, W, Shaw, C, Sproviero, W, Tazelaar, G, van Damme, P, van den Berg, L, van Eijk, K, van Es, M, Veldink, J, Zatz, M, Bauer, D, Twine, N, Rogaeva, E, Zinman, L, Brice, A, Feldman, E, Ludolph, A, Weishaupt, J, Trojanowski, J, Stone, D, Tienari, P, Chiò, A, Traynor, B, Nicolas, Aude, Kenna, Kevin P., Renton, Alan E., Ticozzi, Nicola, Faghri, Faraz, Chia, Ruth, Dominov, Janice A., Kenna, Brendan J., Nalls, Mike A., Keagle, Pamela, Rivera, Alberto M., van Rheenen, Wouter, Murphy, Natalie A., van Vugt, Joke J. F. A., Geiger, Joshua T., van der Spek, Rick, Pliner, Hannah A., Shankaracharya, null, Smith, Bradley N., Marangi, Giuseppe, Topp, Simon D., Abramzon, Yevgeniya, Gkazi, Athina Soragia, Eicher, John D., Kenna, Aoife, Logullo, Francesco O., Simone, Isabella, Logroscino, Giancarlo, Salvi, Fabrizio, Bartolomei, Ilaria, Borghero, Giuseppe, Murru, Maria Rita, Costantino, Emanuela, Pani, Carla, Puddu, Roberta, Caredda, Carla, Piras, Valeria, Tranquilli, Stefania, Cuccu, Stefania, Corongiu, Daniela, Melis, Maurizio, Milia, Antonio, Marrosu, Francesco, Marrosu, Maria Giovanna, Floris, Gianluca, Cannas, Antonino, Capasso, Margherita, Caponnetto, Claudia, Mancardi, Gianluigi, Origone, Paola, Mandich, Paola, Conforti, Francesca L., Cavallaro, Sebastiano, Mora, Gabriele, Marinou, Kalliopi, Sideri, Riccardo, Penco, Silvana, Mosca, Lorena, Lunetta, Christian, Pinter, Giuseppe Lauria, Corbo, Massimo, Riva, Nilo, Carrera, Paola, Volanti, Paolo, Mandrioli, Jessica, Fini, Nicola, Fasano, Antonio, Tremolizzo, Lucio, Arosio, Alessandro, Ferrarese, Carlo, Trojsi, Francesca, Tedeschi, Gioacchino, Monsurrò, Maria Rosaria, Piccirillo, Giovanni, Femiano, Cinzia, Ticca, Anna, Ortu, Enzo, La Bella, Vincenzo, Spataro, Rossella, Colletti, Tiziana, Sabatelli, Mario, Zollino, Marcella, Conte, Amelia, Luigetti, Marco, Lattante, Serena, Santarelli, Marialuisa, Petrucci, Antonio, Pugliatti, Maura, Pirisi, Angelo, Parish, Leslie D., Occhineri, Patrizia, Giannini, Fabio, Battistini, Stefania, Ricci, Claudia, Benigni, Michele, Cau, Tea B., Loi, Daniela, Calvo, Andrea, Moglia, Cristina, Brunetti, Maura, Barberis, Marco, Restagno, Gabriella, Casale, Federico, Marrali, Giuseppe, Fuda, Giuseppe, Ossola, Irene, Cammarosano, Stefania, Canosa, Antonio, Ilardi, Antonio, Manera, Umberto, Grassano, Maurizio, Tanel, Raffaella, Pisano, Fabrizio, Mazzini, Letizia, Messina, Sonia, D'Alfonso, Sandra, Corrado, Lucia, Ferrucci, Luigi, Harms, Matthew B., Goldstein, David B., Shneider, Neil A., Goutman, Stephen, Simmons, Zachary, Miller, Timothy M., Chandran, Siddharthan, Pal, Suvankar, Manousakis, George, Appel, Stanley, Simpson, Ericka, Wang, Leo, Baloh, Robert H., Gibson, Summer, Bedlack, Richard S., Lacomis, David, Sareen, Dhruv, Sherman, Alexander, Bruijn, Lucie, Penny, Michelle, Moreno, Cristiane de Araujo Martins, Kamalakaran, Sitharthan, Allen, Andrew S., Boone, Braden E., Brown, Robert, Carulli, John P., Chesi, Alessandra, Chung, Wendy K., Cirulli, Elizabeth T., Cooper, Gregory M., Couthouis, Julien, Day-Williams, Aaron G., Dion, Patrick A., Gitler, Aaron D., Glass, Jonathan D., Han, Yujun, Harris, Tim, Hayes, Sebastian D., Jones, Angela L., Keebler, Jonathan, Krueger, Brian J., Lasseigne, Brittany N., Levy, Shawn E., Lu, Yi-Fan, Maniatis, Tom, McKenna-Yasek, Diane, Myers, Richard M., Petrovski, Slavé, Pulst, Stefan M., Raphael, Alya R., Ravits, John M., Ren, Zhong, Rouleau, Guy A., Sapp, Peter C., Sims, Katherine B., Staropoli, John F., Waite, Lindsay L., Wang, Quanli, Wimbish, Jack R., Xin, Winnie W., Phatnani, Hemali, Kwan, Justin, Broach, James R., Arcila-Londono, Ximena, Lee, Edward B., Van Deerlin, Vivianna M., Fraenkel, Ernest, Ostrow, Lyle W., Baas, Frank, Zaitlen, Noah, Berry, James D., Malaspina, Andrea, Fratta, Pietro, Cox, Gregory A., Thompson, Leslie M., Finkbeiner, Steven, Dardiotis, Efthimios, Hornstein, Eran, MacGowan, Daniel J., Heiman-Patterson, Terry, Hammell, Molly G., Patsopoulos, Nikolaos A., Dubnau, Joshua, Nath, Avindra, Musunuri, Rajeeva Lochan, Evani, Uday Shankar, Abhyankar, Avinash, Zody, Michael C., Kaye, Julia, Wyman, Stacia, LeNail, Alexander, Lima, Leandro, Rothstein, Jeffrey D., Svendsen, Clive N., Van Eyk, Jenny, Maragakis, Nicholas J., Kolb, Stephen J., Cudkowicz, Merit, Baxi, Emily, Wyman, Stacia K., Van Eyk, Jennifer E., Benatar, Michael, Taylor, J. Paul, Wu, Gang, Rampersaud, Evadnie, Wuu, Joanne, Rademakers, Rosa, Züchner, Stephan, Schule, Rebecca, McCauley, Jacob, Hussain, Sumaira, Cooley, Anne, Wallace, Marielle, Clayman, Christine, Barohn, Richard, Statland, Jeffrey, Ravits, John, Swenson, Andrea, Jackson, Carlayne, Trivedi, Jaya, Khan, Shaida, Katz, Jonathan, Jenkins, Liberty, Burns, Ted, Gwathmey, Kelly, Caress, James, McMillan, Corey, Elman, Lauren, Pioro, Erik, Heckmann, Jeannine, So, Yuen, Walk, David, Maiser, Samuel, Zhang, Jinghui, Silani, Vincenzo, Gellera, Cinzia, Ratti, Antonia, Taroni, Franco, Lauria, Giuseppe, Verde, Federico, Fogh, Isabella, Tiloca, Cinzia, Comi, Giacomo P., Sorarù, Gianni, Cereda, Cristina, De Marchi, Fabiola, Corti, Stefania, Ceroni, Mauro, Siciliano, Gabriele, Filosto, Massimiliano, Inghilleri, Maurizio, Peverelli, Silvia, Colombrita, Claudia, Poletti, Barbara, Maderna, Luca, Del Bo, Roberto, Gagliardi, Stella, Querin, Giorgia, Bertolin, Cinzia, Pensato, Viviana, Castellotti, Barbara, Camu, William, Mouzat, Kevin, Lumbroso, Serge, Corcia, Philippe, Meininger, Vincent, Besson, Gérard, Lagrange, Emmeline, Clavelou, Pierre, Guy, Nathalie, Couratier, Philippe, Vourch, Patrick, Danel, Véronique, Bernard, Emilien, Lemasson, Gwendal, Laaksovirta, Hannu, Myllykangas, Liisa, Jansson, Lilja, Valori, Miko, Ealing, John, Hamdalla, Hisham, Rollinson, Sara, Pickering-Brown, Stuart, Orrell, Richard W., Sidle, Katie C., Hardy, John, Singleton, Andrew B., Johnson, Janel O., Arepalli, Sampath, Polak, Meraida, Asress, Seneshaw, Al-Sarraj, Safa, King, Andrew, Troakes, Claire, Vance, Caroline, de Belleroche, Jacqueline, ten Asbroek, Anneloor L. M. A., Muñoz-Blanco, José Luis, Hernandez, Dena G., Ding, Jinhui, Gibbs, J. Raphael, Scholz, Sonja W., Floeter, Mary Kay, Campbell, Roy H., Landi, Francesco, Bowser, Robert, MacGowan, Daniel J. L., Kirby, Janine, Pioro, Erik P., Pamphlett, Roger, Broach, James, Gerhard, Glenn, Dunckley, Travis L., Brady, Christopher B., Kowall, Neil W., Troncoso, Juan C., Le Ber, Isabelle, Heiman-Patterson, Terry D., Kamel, Freya, Van Den Bosch, Ludo, Strom, Tim M., Meitinger, Thomas, Shatunov, Aleksey, Van Eijk, Kristel R., de Carvalho, Mamede, Kooyman, Maarten, Middelkoop, Bas, Moisse, Mattieu, McLaughlin, Russell L., Van Es, Michael A., Weber, Markus, Boylan, Kevin B., Van Blitterswijk, Marka, Morrison, Karen E., Basak, A. Nazli, Mora, Jesús S., Drory, Vivian E., Shaw, Pamela J., Turner, Martin R., Talbot, Kevin, Hardiman, Orla, Williams, Kelly L., Fifita, Jennifer A., Nicholson, Garth A., Blair, Ian P., Esteban-Pérez, Jesús, García-Redondo, Alberto, Al-Chalabi, Ammar, Al Kheifat, Ahmad, Andersen, Peter, Chio, Adriano, Cooper-Knock, Jonathan, Dekker, Annelot, Drory, Vivian, Redondo, Alberto Garcia, Gotkine, Marc, Hide, Winston, Iacoangeli, Alfredo, Glass, Jonathan, Kenna, Kevin, Kiernan, Matthew, Landers, John, McLaughlin, Russell, Mill, Jonathan, Neto, Miguel Mitne, Pardina, Jesus Mora, Morrison, Karen, Newhouse, Stephen, Pinto, Susana, Pulit, Sara, Robberecht, Wim, Shaw, Pamela, Shaw, Chris, Sproviero, William, Tazelaar, Gijs, van Damme, Philip, van den Berg, Leonard, van Eijk, Kristel, van Es, Michael, van Vugt, Joke, Veldink, Jan, Zatz, Mayana, Bauer, Denis C., Twine, Natalie A., Rogaeva, Ekaterina, Zinman, Lorne, Brice, Alexis, Goutman, Stephen A., Feldman, Eva L., Gibson, Summer B., Ludolph, Albert C., Andersen, Peter M., Weishaupt, Jochen H., Trojanowski, John Q., Brown, Robert H., van den Berg, Leonard H., Veldink, Jan H., Stone, David J., Tienari, Pentti, Chiò, Adriano, Shaw, Christopher E., Traynor, Bryan J., Landers, John E., Nicolas, A, Kenna, K, Renton, A, Ticozzi, N, Faghri, F, Chia, R, Dominov, J, Kenna, B, Nalls, M, Keagle, P, Rivera, A, van Rheenen, W, Murphy, N, van Vugt, J, Geiger, J, van der Spek, R, Pliner, H, Shankaracharya, N, Smith, B, Marangi, G, Topp, S, Abramzon, Y, Gkazi, A, Eicher, J, Kenna, A, Logullo, F, Simone, I, Logroscino, G, Salvi, F, Bartolomei, I, Borghero, G, Murru, M, Costantino, E, Pani, C, Puddu, R, Caredda, C, Piras, V, Tranquilli, S, Cuccu, S, Corongiu, D, Melis, M, Milia, A, Marrosu, F, Marrosu, M, Floris, G, Cannas, A, Capasso, M, Caponnetto, C, Mancardi, G, Origone, P, Mandich, P, Conforti, F, Cavallaro, S, Mora, G, Marinou, K, Sideri, R, Penco, S, Mosca, L, Lunetta, C, Pinter, G, Corbo, M, Riva, N, Carrera, P, Volanti, P, Mandrioli, J, Fini, N, Fasano, A, Tremolizzo, L, Arosio, A, Ferrarese, C, Trojsi, F, Tedeschi, G, Monsurrò, M, Piccirillo, G, Femiano, C, Ticca, A, Ortu, E, La Bella, V, Spataro, R, Colletti, T, Sabatelli, M, Zollino, M, Conte, A, Luigetti, M, Lattante, S, Santarelli, M, Petrucci, A, Pugliatti, M, Pirisi, A, Parish, L, Occhineri, P, Giannini, F, Battistini, S, Ricci, C, Benigni, M, Cau, T, Loi, D, Calvo, A, Moglia, C, Brunetti, M, Barberis, M, Restagno, G, Casale, F, Marrali, G, Fuda, G, Ossola, I, Cammarosano, S, Canosa, A, Ilardi, A, Manera, U, Grassano, M, Tanel, R, Pisano, F, Mazzini, L, Messina, S, D'Alfonso, S, Corrado, L, Ferrucci, L, Harms, M, Goldstein, D, Shneider, N, Goutman, S, Simmons, Z, Miller, T, Chandran, S, Pal, S, Manousakis, G, Appel, S, Simpson, E, Wang, L, Baloh, R, Gibson, S, Bedlack, R, Lacomis, D, Sareen, D, Sherman, A, Bruijn, L, Penny, M, Moreno, C, Kamalakaran, S, Allen, A, Boone, B, Brown, R, Carulli, J, Chesi, A, Chung, W, Cirulli, E, Cooper, G, Couthouis, J, Day-Williams, A, Dion, P, Gitler, A, Glass, J, Han, Y, Harris, T, Hayes, S, Jones, A, Keebler, J, Krueger, B, Lasseigne, B, Levy, S, Lu, Y, Maniatis, T, McKenna-Yasek, D, Myers, R, Petrovski, S, Pulst, S, Raphael, A, Ravits, J, Ren, Z, Rouleau, G, Sapp, P, Sims, K, Staropoli, J, Waite, L, Wang, Q, Wimbish, J, Xin, W, Phatnani, H, Kwan, J, Broach, J, Arcila-Londono, X, Lee, E, Van Deerlin, V, Fraenkel, E, Ostrow, L, Baas, F, Zaitlen, N, Berry, J, Malaspina, A, Fratta, P, Cox, G, Thompson, L, Finkbeiner, S, Dardiotis, E, Hornstein, E, Macgowan, D, Heiman-Patterson, T, Hammell, M, Patsopoulos, N, Dubnau, J, Nath, A, Musunuri, R, Evani, U, Abhyankar, A, Zody, M, Kaye, J, Wyman, S, Lenail, A, Lima, L, Rothstein, J, Svendsen, C, Van Eyk, J, Maragakis, N, Kolb, S, Cudkowicz, M, Baxi, E, Benatar, M, Taylor, J, Wu, G, Rampersaud, E, Wuu, J, Rademakers, R, Züchner, S, Schule, R, Mccauley, J, Hussain, S, Cooley, A, Wallace, M, Clayman, C, Barohn, R, Statland, J, Swenson, A, Jackson, C, Trivedi, J, Khan, S, Katz, J, Jenkins, L, Burns, T, Gwathmey, K, Caress, J, Mcmillan, C, Elman, L, Pioro, E, Heckmann, J, So, Y, Walk, D, Maiser, S, Zhang, J, Silani, V, Gellera, C, Ratti, A, Taroni, F, Lauria, G, Verde, F, Fogh, I, Tiloca, C, Comi, G, Sorarù, G, Cereda, C, De Marchi, F, Corti, S, Ceroni, M, Siciliano, G, Filosto, M, Inghilleri, M, Peverelli, S, Colombrita, C, Poletti, B, Maderna, L, Del Bo, R, Gagliardi, S, Querin, G, Bertolin, C, Pensato, V, Castellotti, B, Camu, W, Mouzat, K, Lumbroso, S, Corcia, P, Meininger, V, Besson, G, Lagrange, E, Clavelou, P, Guy, N, Couratier, P, Vourch, P, Danel, V, Bernard, E, Lemasson, G, Laaksovirta, H, Myllykangas, L, Jansson, L, Valori, M, Ealing, J, Hamdalla, H, Rollinson, S, Pickering-Brown, S, Orrell, R, Sidle, K, Hardy, J, Singleton, A, Johnson, J, Arepalli, S, Polak, M, Asress, S, Al-Sarraj, S, King, A, Troakes, C, Vance, C, de Belleroche, J, ten Asbroek, A, Muñoz-Blanco, J, Hernandez, D, Ding, J, Gibbs, J, Scholz, S, Floeter, M, Campbell, R, Landi, F, Bowser, R, Kirby, J, Pamphlett, R, Gerhard, G, Dunckley, T, Brady, C, Kowall, N, Troncoso, J, Le Ber, I, Kamel, F, Van Den Bosch, L, Strom, T, Meitinger, T, Shatunov, A, Van Eijk, K, de Carvalho, M, Kooyman, M, Middelkoop, B, Moisse, M, Mclaughlin, R, Van Es, M, Weber, M, Boylan, K, Van Blitterswijk, M, Morrison, K, Basak, A, Mora, J, Drory, V, Shaw, P, Turner, M, Talbot, K, Hardiman, O, Williams, K, Fifita, J, Nicholson, G, Blair, I, Esteban-Pérez, J, García-Redondo, A, Al-Chalabi, A, Al Kheifat, A, Andersen, P, Chio, A, Cooper-Knock, J, Dekker, A, Redondo, A, Gotkine, M, Hide, W, Iacoangeli, A, Kiernan, M, Landers, J, Mill, J, Neto, M, Pardina, J, Newhouse, S, Pinto, S, Pulit, S, Robberecht, W, Shaw, C, Sproviero, W, Tazelaar, G, van Damme, P, van den Berg, L, van Eijk, K, van Es, M, Veldink, J, Zatz, M, Bauer, D, Twine, N, Rogaeva, E, Zinman, L, Brice, A, Feldman, E, Ludolph, A, Weishaupt, J, Trojanowski, J, Stone, D, Tienari, P, Chiò, A, Traynor, B, Nicolas, Aude, Kenna, Kevin P., Renton, Alan E., Ticozzi, Nicola, Faghri, Faraz, Chia, Ruth, Dominov, Janice A., Kenna, Brendan J., Nalls, Mike A., Keagle, Pamela, Rivera, Alberto M., van Rheenen, Wouter, Murphy, Natalie A., van Vugt, Joke J. F. A., Geiger, Joshua T., van der Spek, Rick, Pliner, Hannah A., Shankaracharya, null, Smith, Bradley N., Marangi, Giuseppe, Topp, Simon D., Abramzon, Yevgeniya, Gkazi, Athina Soragia, Eicher, John D., Kenna, Aoife, Logullo, Francesco O., Simone, Isabella, Logroscino, Giancarlo, Salvi, Fabrizio, Bartolomei, Ilaria, Borghero, Giuseppe, Murru, Maria Rita, Costantino, Emanuela, Pani, Carla, Puddu, Roberta, Caredda, Carla, Piras, Valeria, Tranquilli, Stefania, Cuccu, Stefania, Corongiu, Daniela, Melis, Maurizio, Milia, Antonio, Marrosu, Francesco, Marrosu, Maria Giovanna, Floris, Gianluca, Cannas, Antonino, Capasso, Margherita, Caponnetto, Claudia, Mancardi, Gianluigi, Origone, Paola, Mandich, Paola, Conforti, Francesca L., Cavallaro, Sebastiano, Mora, Gabriele, Marinou, Kalliopi, Sideri, Riccardo, Penco, Silvana, Mosca, Lorena, Lunetta, Christian, Pinter, Giuseppe Lauria, Corbo, Massimo, Riva, Nilo, Carrera, Paola, Volanti, Paolo, Mandrioli, Jessica, Fini, Nicola, Fasano, Antonio, Tremolizzo, Lucio, Arosio, Alessandro, Ferrarese, Carlo, Trojsi, Francesca, Tedeschi, Gioacchino, Monsurrò, Maria Rosaria, Piccirillo, Giovanni, Femiano, Cinzia, Ticca, Anna, Ortu, Enzo, La Bella, Vincenzo, Spataro, Rossella, Colletti, Tiziana, Sabatelli, Mario, Zollino, Marcella, Conte, Amelia, Luigetti, Marco, Lattante, Serena, Santarelli, Marialuisa, Petrucci, Antonio, Pugliatti, Maura, Pirisi, Angelo, Parish, Leslie D., Occhineri, Patrizia, Giannini, Fabio, Battistini, Stefania, Ricci, Claudia, Benigni, Michele, Cau, Tea B., Loi, Daniela, Calvo, Andrea, Moglia, Cristina, Brunetti, Maura, Barberis, Marco, Restagno, Gabriella, Casale, Federico, Marrali, Giuseppe, Fuda, Giuseppe, Ossola, Irene, Cammarosano, Stefania, Canosa, Antonio, Ilardi, Antonio, Manera, Umberto, Grassano, Maurizio, Tanel, Raffaella, Pisano, Fabrizio, Mazzini, Letizia, Messina, Sonia, D'Alfonso, Sandra, Corrado, Lucia, Ferrucci, Luigi, Harms, Matthew B., Goldstein, David B., Shneider, Neil A., Goutman, Stephen, Simmons, Zachary, Miller, Timothy M., Chandran, Siddharthan, Pal, Suvankar, Manousakis, George, Appel, Stanley, Simpson, Ericka, Wang, Leo, Baloh, Robert H., Gibson, Summer, Bedlack, Richard S., Lacomis, David, Sareen, Dhruv, Sherman, Alexander, Bruijn, Lucie, Penny, Michelle, Moreno, Cristiane de Araujo Martins, Kamalakaran, Sitharthan, Allen, Andrew S., Boone, Braden E., Brown, Robert, Carulli, John P., Chesi, Alessandra, Chung, Wendy K., Cirulli, Elizabeth T., Cooper, Gregory M., Couthouis, Julien, Day-Williams, Aaron G., Dion, Patrick A., Gitler, Aaron D., Glass, Jonathan D., Han, Yujun, Harris, Tim, Hayes, Sebastian D., Jones, Angela L., Keebler, Jonathan, Krueger, Brian J., Lasseigne, Brittany N., Levy, Shawn E., Lu, Yi-Fan, Maniatis, Tom, McKenna-Yasek, Diane, Myers, Richard M., Petrovski, Slavé, Pulst, Stefan M., Raphael, Alya R., Ravits, John M., Ren, Zhong, Rouleau, Guy A., Sapp, Peter C., Sims, Katherine B., Staropoli, John F., Waite, Lindsay L., Wang, Quanli, Wimbish, Jack R., Xin, Winnie W., Phatnani, Hemali, Kwan, Justin, Broach, James R., Arcila-Londono, Ximena, Lee, Edward B., Van Deerlin, Vivianna M., Fraenkel, Ernest, Ostrow, Lyle W., Baas, Frank, Zaitlen, Noah, Berry, James D., Malaspina, Andrea, Fratta, Pietro, Cox, Gregory A., Thompson, Leslie M., Finkbeiner, Steven, Dardiotis, Efthimios, Hornstein, Eran, MacGowan, Daniel J., Heiman-Patterson, Terry, Hammell, Molly G., Patsopoulos, Nikolaos A., Dubnau, Joshua, Nath, Avindra, Musunuri, Rajeeva Lochan, Evani, Uday Shankar, Abhyankar, Avinash, Zody, Michael C., Kaye, Julia, Wyman, Stacia, LeNail, Alexander, Lima, Leandro, Rothstein, Jeffrey D., Svendsen, Clive N., Van Eyk, Jenny, Maragakis, Nicholas J., Kolb, Stephen J., Cudkowicz, Merit, Baxi, Emily, Wyman, Stacia K., Van Eyk, Jennifer E., Benatar, Michael, Taylor, J. Paul, Wu, Gang, Rampersaud, Evadnie, Wuu, Joanne, Rademakers, Rosa, Züchner, Stephan, Schule, Rebecca, McCauley, Jacob, Hussain, Sumaira, Cooley, Anne, Wallace, Marielle, Clayman, Christine, Barohn, Richard, Statland, Jeffrey, Ravits, John, Swenson, Andrea, Jackson, Carlayne, Trivedi, Jaya, Khan, Shaida, Katz, Jonathan, Jenkins, Liberty, Burns, Ted, Gwathmey, Kelly, Caress, James, McMillan, Corey, Elman, Lauren, Pioro, Erik, Heckmann, Jeannine, So, Yuen, Walk, David, Maiser, Samuel, Zhang, Jinghui, Silani, Vincenzo, Gellera, Cinzia, Ratti, Antonia, Taroni, Franco, Lauria, Giuseppe, Verde, Federico, Fogh, Isabella, Tiloca, Cinzia, Comi, Giacomo P., Sorarù, Gianni, Cereda, Cristina, De Marchi, Fabiola, Corti, Stefania, Ceroni, Mauro, Siciliano, Gabriele, Filosto, Massimiliano, Inghilleri, Maurizio, Peverelli, Silvia, Colombrita, Claudia, Poletti, Barbara, Maderna, Luca, Del Bo, Roberto, Gagliardi, Stella, Querin, Giorgia, Bertolin, Cinzia, Pensato, Viviana, Castellotti, Barbara, Camu, William, Mouzat, Kevin, Lumbroso, Serge, Corcia, Philippe, Meininger, Vincent, Besson, Gérard, Lagrange, Emmeline, Clavelou, Pierre, Guy, Nathalie, Couratier, Philippe, Vourch, Patrick, Danel, Véronique, Bernard, Emilien, Lemasson, Gwendal, Laaksovirta, Hannu, Myllykangas, Liisa, Jansson, Lilja, Valori, Miko, Ealing, John, Hamdalla, Hisham, Rollinson, Sara, Pickering-Brown, Stuart, Orrell, Richard W., Sidle, Katie C., Hardy, John, Singleton, Andrew B., Johnson, Janel O., Arepalli, Sampath, Polak, Meraida, Asress, Seneshaw, Al-Sarraj, Safa, King, Andrew, Troakes, Claire, Vance, Caroline, de Belleroche, Jacqueline, ten Asbroek, Anneloor L. M. A., Muñoz-Blanco, José Luis, Hernandez, Dena G., Ding, Jinhui, Gibbs, J. Raphael, Scholz, Sonja W., Floeter, Mary Kay, Campbell, Roy H., Landi, Francesco, Bowser, Robert, MacGowan, Daniel J. L., Kirby, Janine, Pioro, Erik P., Pamphlett, Roger, Broach, James, Gerhard, Glenn, Dunckley, Travis L., Brady, Christopher B., Kowall, Neil W., Troncoso, Juan C., Le Ber, Isabelle, Heiman-Patterson, Terry D., Kamel, Freya, Van Den Bosch, Ludo, Strom, Tim M., Meitinger, Thomas, Shatunov, Aleksey, Van Eijk, Kristel R., de Carvalho, Mamede, Kooyman, Maarten, Middelkoop, Bas, Moisse, Mattieu, McLaughlin, Russell L., Van Es, Michael A., Weber, Markus, Boylan, Kevin B., Van Blitterswijk, Marka, Morrison, Karen E., Basak, A. Nazli, Mora, Jesús S., Drory, Vivian E., Shaw, Pamela J., Turner, Martin R., Talbot, Kevin, Hardiman, Orla, Williams, Kelly L., Fifita, Jennifer A., Nicholson, Garth A., Blair, Ian P., Esteban-Pérez, Jesús, García-Redondo, Alberto, Al-Chalabi, Ammar, Al Kheifat, Ahmad, Andersen, Peter, Chio, Adriano, Cooper-Knock, Jonathan, Dekker, Annelot, Drory, Vivian, Redondo, Alberto Garcia, Gotkine, Marc, Hide, Winston, Iacoangeli, Alfredo, Glass, Jonathan, Kenna, Kevin, Kiernan, Matthew, Landers, John, McLaughlin, Russell, Mill, Jonathan, Neto, Miguel Mitne, Pardina, Jesus Mora, Morrison, Karen, Newhouse, Stephen, Pinto, Susana, Pulit, Sara, Robberecht, Wim, Shaw, Pamela, Shaw, Chris, Sproviero, William, Tazelaar, Gijs, van Damme, Philip, van den Berg, Leonard, van Eijk, Kristel, van Es, Michael, van Vugt, Joke, Veldink, Jan, Zatz, Mayana, Bauer, Denis C., Twine, Natalie A., Rogaeva, Ekaterina, Zinman, Lorne, Brice, Alexis, Goutman, Stephen A., Feldman, Eva L., Gibson, Summer B., Ludolph, Albert C., Andersen, Peter M., Weishaupt, Jochen H., Trojanowski, John Q., Brown, Robert H., van den Berg, Leonard H., Veldink, Jan H., Stone, David J., Tienari, Pentti, Chiò, Adriano, Shaw, Christopher E., Traynor, Bryan J., and Landers, John E.
Abstract: To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS. Using a large-scale genome-wide association study and exome sequencing, we identified KIF5A as a novel gene associated with ALS. Our data broaden the phenotype resulting from mutations in KIF5A and highlight the importance of cytoskeletal defects in the pathogenesis of ALS.
Published: 2018

17. Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

Author: Nicolas, Aude, Kenna, Kevin P., Renton, Alan E., Ticozzi, Nicola, Faghri, Faraz, Chia, Ruth, Dominov, Janice A., Kenna, Brendan J., Nalls, Mike A., Keagle, Pamela, Rivera, Alberto M., van Rheenen, Wouter, Murphy, Natalie A., van Vugt, Joke J. F. A., Geiger, Joshua T., van der Spek, Rick A., Pliner, Hannah A., Shankaracharya, Smith, Bradley N., Marangi, Giuseppe, Topp, Simon D., Abramzon, Yevgeniya, Gkazi, Athina Soragia, Eicher, John D., Kenna, Aoife, Mora, Gabriele, Calvo, Andrea, Mazzini, Letizia, Riva, Nilo, Mandrioli, Jessica, Caponnetto, Claudia, Battistini, Stefania, Volanti, Paolo, La Bella, Vincenzo, Conforti, Francesca L., Borghero, Giuseppe, Messina, Sonia, Simone, Isabella L., Trojsi, Francesca, Salvi, Fabrizio, Logullo, Francesco O., D'Alfonso, Sandra, Corrado, Lucia, Capasso, Margherita, Ferrucci, Luigi, Moreno, Cristiane de Araujo Martins, Kamalakaran, Sitharthan, Goldstein, David B., Gitler, Aaron D., Harris, Tim, Myers, Richard M., Phatnani, Hemali, Musunuri, Rajeeva Lochan, Evani, Uday Shankar, Abhyankar, Avinash, Zody, Michael C., Kaye, Julia, Finkbeiner, Steven, Wyman, Stacia K., LeNail, Alex, Lima, Leandro, Fraenkel, Ernest, Svendsen, Clive N., Thompson, Leslie M., Van Eyk, Jennifer E., Berry, James D., Miller, Timothy M., Kolb, Stephen J., Cudkowicz, Merit, Baxi, Emily, Benatar, Michael, Taylor, J. Paul, Rampersaud, Evadnie, Wu, Gang, Wuu, Joanne, Lauria, Giuseppe, Verde, Federico, Fogh, Isabella, Tiloca, Cinzia, Comi, Giacomo P., Soraru, Gianni, Cereda, Cristina, Corcia, Philippe, Laaksovirta, Hannu, Myllykangas, Liisa, Jansson, Lilja, Valori, Miko, Ealing, John, Hamdalla, Hisham, Rollinson, Sara, Pickering-Brown, Stuart, Orrell, Richard W., Sidle, Katie C., Malaspina, Andrea, Hardy, John, Singleton, Andrew B., Johnson, Janel O., Arepalli, Sampath, Sapp, Peter C., McKenna-Yasek, Diane, Polak, Meraida, Asress, Seneshaw, Al-Sarraj, Safa, King, Andrew, Troakes, Claire, Vance, Caroline, de Belleroche, Jacqueline, Baas, Frank, ten Asbroek, Anneloor L. M. A., Luis Munoz-Blanco, Jose, Hernandez, Dena G., Ding, Jinhui, Gibbs, J. Raphael, Scholz, Sonja W., Floeter, Mary Kay, Campbell, Roy H., Landi, Francesco, Bowser, Robert, Pulst, Stefan M., Ravits, John M., MacGowan, Daniel J. L., Kirby, Janine, Pioro, Erik P., Pamphlett, Roger, Broach, James, Gerhard, Glenn, Dunckley, Travis L., Brady, Christopher B., Kowall, Neil W., Troncoso, Juan C., Le Ber, Isabelle, Mouzat, Kevin, Lumbroso, Serge, Heiman-Patterson, Terry D., Kamel, Freya, Van Den Bosch, Ludo, Baloh, Robert H., Strom, Tim M., Meitinger, Thomas, Shatunov, Aleksey, Van Eijk, Kristel R., de Carvalho, Mamede, Kooyman, Maarten, Middelkoop, Bas, Moisse, Matthieu, McLaughlin, Russell L., Van Es, Michael A., Weber, Markus, Boylan, Kevin B., Van Blitterswijk, Marka, Rademakers, Rosa, Morrison, Karen E., Basak, A. Nazli, Mora, Jesus S., Drory, Vivian E., Shaw, Pamela J., Turner, Martin R., Talbot, Kevin, Hardiman, Orla, Williams, Kelly L., Fifita, Jennifer A., Nicholson, Garth A., Blair, Ian P., Rouleau, Guy A., Esteban-Perez, Jesus, Garcia-Redondo, Alberto, Al-Chalabi, Ammar, Rogaeva, Ekaterina, Zinman, Lorne, Ostrow, Lyle W., Maragakis, Nicholas J., Rothstein, Jeffrey D., Simmons, Zachary, Cooper-Knock, Johnathan, Brice, Alexis, Goutman, Stephen A., Feldman, Eva L., Gibson, Summer B., Taroni, Franco, Ratti, Antonia, Gellera, Cinzia, Van Damme, Philip, Robberecht, Wim, Fratta, Pietro, Sabatelli, Mario, Lunetta, Christian, Ludolph, Albert C., Andersen, Peter M., Weishaupt, Jochen H., Camu, William, Trojanowski, John Q., Van Deerlin, Vivianna M., Brown, Robert H., Jr., van den Berg, Leonard H., Veldink, Jan H., Harms, Matthew B., Glass, Jonathan D., Stone, David J., Tienari, Pentti, Silani, Vincenzo, Chio, Adriano, Shaw, Christopher E., Traynor, Bryan J., Landers, John E., Nicolas, Aude, Kenna, Kevin P., Renton, Alan E., Ticozzi, Nicola, Faghri, Faraz, Chia, Ruth, Dominov, Janice A., Kenna, Brendan J., Nalls, Mike A., Keagle, Pamela, Rivera, Alberto M., van Rheenen, Wouter, Murphy, Natalie A., van Vugt, Joke J. F. A., Geiger, Joshua T., van der Spek, Rick A., Pliner, Hannah A., Shankaracharya, Smith, Bradley N., Marangi, Giuseppe, Topp, Simon D., Abramzon, Yevgeniya, Gkazi, Athina Soragia, Eicher, John D., Kenna, Aoife, Mora, Gabriele, Calvo, Andrea, Mazzini, Letizia, Riva, Nilo, Mandrioli, Jessica, Caponnetto, Claudia, Battistini, Stefania, Volanti, Paolo, La Bella, Vincenzo, Conforti, Francesca L., Borghero, Giuseppe, Messina, Sonia, Simone, Isabella L., Trojsi, Francesca, Salvi, Fabrizio, Logullo, Francesco O., D'Alfonso, Sandra, Corrado, Lucia, Capasso, Margherita, Ferrucci, Luigi, Moreno, Cristiane de Araujo Martins, Kamalakaran, Sitharthan, Goldstein, David B., Gitler, Aaron D., Harris, Tim, Myers, Richard M., Phatnani, Hemali, Musunuri, Rajeeva Lochan, Evani, Uday Shankar, Abhyankar, Avinash, Zody, Michael C., Kaye, Julia, Finkbeiner, Steven, Wyman, Stacia K., LeNail, Alex, Lima, Leandro, Fraenkel, Ernest, Svendsen, Clive N., Thompson, Leslie M., Van Eyk, Jennifer E., Berry, James D., Miller, Timothy M., Kolb, Stephen J., Cudkowicz, Merit, Baxi, Emily, Benatar, Michael, Taylor, J. Paul, Rampersaud, Evadnie, Wu, Gang, Wuu, Joanne, Lauria, Giuseppe, Verde, Federico, Fogh, Isabella, Tiloca, Cinzia, Comi, Giacomo P., Soraru, Gianni, Cereda, Cristina, Corcia, Philippe, Laaksovirta, Hannu, Myllykangas, Liisa, Jansson, Lilja, Valori, Miko, Ealing, John, Hamdalla, Hisham, Rollinson, Sara, Pickering-Brown, Stuart, Orrell, Richard W., Sidle, Katie C., Malaspina, Andrea, Hardy, John, Singleton, Andrew B., Johnson, Janel O., Arepalli, Sampath, Sapp, Peter C., McKenna-Yasek, Diane, Polak, Meraida, Asress, Seneshaw, Al-Sarraj, Safa, King, Andrew, Troakes, Claire, Vance, Caroline, de Belleroche, Jacqueline, Baas, Frank, ten Asbroek, Anneloor L. M. A., Luis Munoz-Blanco, Jose, Hernandez, Dena G., Ding, Jinhui, Gibbs, J. Raphael, Scholz, Sonja W., Floeter, Mary Kay, Campbell, Roy H., Landi, Francesco, Bowser, Robert, Pulst, Stefan M., Ravits, John M., MacGowan, Daniel J. L., Kirby, Janine, Pioro, Erik P., Pamphlett, Roger, Broach, James, Gerhard, Glenn, Dunckley, Travis L., Brady, Christopher B., Kowall, Neil W., Troncoso, Juan C., Le Ber, Isabelle, Mouzat, Kevin, Lumbroso, Serge, Heiman-Patterson, Terry D., Kamel, Freya, Van Den Bosch, Ludo, Baloh, Robert H., Strom, Tim M., Meitinger, Thomas, Shatunov, Aleksey, Van Eijk, Kristel R., de Carvalho, Mamede, Kooyman, Maarten, Middelkoop, Bas, Moisse, Matthieu, McLaughlin, Russell L., Van Es, Michael A., Weber, Markus, Boylan, Kevin B., Van Blitterswijk, Marka, Rademakers, Rosa, Morrison, Karen E., Basak, A. Nazli, Mora, Jesus S., Drory, Vivian E., Shaw, Pamela J., Turner, Martin R., Talbot, Kevin, Hardiman, Orla, Williams, Kelly L., Fifita, Jennifer A., Nicholson, Garth A., Blair, Ian P., Rouleau, Guy A., Esteban-Perez, Jesus, Garcia-Redondo, Alberto, Al-Chalabi, Ammar, Rogaeva, Ekaterina, Zinman, Lorne, Ostrow, Lyle W., Maragakis, Nicholas J., Rothstein, Jeffrey D., Simmons, Zachary, Cooper-Knock, Johnathan, Brice, Alexis, Goutman, Stephen A., Feldman, Eva L., Gibson, Summer B., Taroni, Franco, Ratti, Antonia, Gellera, Cinzia, Van Damme, Philip, Robberecht, Wim, Fratta, Pietro, Sabatelli, Mario, Lunetta, Christian, Ludolph, Albert C., Andersen, Peter M., Weishaupt, Jochen H., Camu, William, Trojanowski, John Q., Van Deerlin, Vivianna M., Brown, Robert H., Jr., van den Berg, Leonard H., Veldink, Jan H., Harms, Matthew B., Glass, Jonathan D., Stone, David J., Tienari, Pentti, Silani, Vincenzo, Chio, Adriano, Shaw, Christopher E., Traynor, Bryan J., and Landers, John E.
Abstract: To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.
Published: 2018
Full Text: View/download PDF

18. Genome-wide Analyses Identify KIF5A as a Novel ALS Gene.

Author: Nicolas, Aude, Nicolas, Aude, Kenna, Kevin P, Renton, Alan E, Ticozzi, Nicola, Faghri, Faraz, Chia, Ruth, Dominov, Janice A, Kenna, Brendan J, Nalls, Mike A, Keagle, Pamela, Rivera, Alberto M, van Rheenen, Wouter, Murphy, Natalie A, van Vugt, Joke JFA, Geiger, Joshua T, Van der Spek, Rick A, Pliner, Hannah A, Shankaracharya, Smith, Bradley N, Marangi, Giuseppe, Topp, Simon D, Abramzon, Yevgeniya, Gkazi, Athina Soragia, Eicher, John D, Kenna, Aoife, ITALSGEN Consortium, Mora, Gabriele, Calvo, Andrea, Mazzini, Letizia, Riva, Nilo, Mandrioli, Jessica, Caponnetto, Claudia, Battistini, Stefania, Volanti, Paolo, La Bella, Vincenzo, Conforti, Francesca L, Borghero, Giuseppe, Messina, Sonia, Simone, Isabella L, Trojsi, Francesca, Salvi, Fabrizio, Logullo, Francesco O, D'Alfonso, Sandra, Corrado, Lucia, Capasso, Margherita, Ferrucci, Luigi, Genomic Translation for ALS Care (GTAC) Consortium, Moreno, Cristiane de Araujo Martins, Kamalakaran, Sitharthan, Goldstein, David B, ALS Sequencing Consortium, Gitler, Aaron D, Harris, Tim, Myers, Richard M, NYGC ALS Consortium, Phatnani, Hemali, Musunuri, Rajeeva Lochan, Evani, Uday Shankar, Abhyankar, Avinash, Zody, Michael C, Answer ALS Foundation, Kaye, Julia, Finkbeiner, Steven, Wyman, Stacia K, LeNail, Alex, Lima, Leandro, Fraenkel, Ernest, Svendsen, Clive N, Thompson, Leslie M, Van Eyk, Jennifer E, Berry, James D, Miller, Timothy M, Kolb, Stephen J, Cudkowicz, Merit, Baxi, Emily, Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium, Benatar, Michael, Taylor, J Paul, Rampersaud, Evadnie, Wu, Gang, Wuu, Joanne, SLAGEN Consortium, Lauria, Giuseppe, Verde, Federico, Fogh, Isabella, Tiloca, Cinzia, Comi, Giacomo P, Sorarù, Gianni, Cereda, Cristina, French ALS Consortium, Corcia, Philippe, Laaksovirta, Hannu, Myllykangas, Liisa, Jansson, Lilja, Valori, Miko, Ealing, John, Hamdalla, Hisham, Rollinson, Sara, Pickering-Brown, Stuart, Orrell, Richard W, Nicolas, Aude, Nicolas, Aude, Kenna, Kevin P, Renton, Alan E, Ticozzi, Nicola, Faghri, Faraz, Chia, Ruth, Dominov, Janice A, Kenna, Brendan J, Nalls, Mike A, Keagle, Pamela, Rivera, Alberto M, van Rheenen, Wouter, Murphy, Natalie A, van Vugt, Joke JFA, Geiger, Joshua T, Van der Spek, Rick A, Pliner, Hannah A, Shankaracharya, Smith, Bradley N, Marangi, Giuseppe, Topp, Simon D, Abramzon, Yevgeniya, Gkazi, Athina Soragia, Eicher, John D, Kenna, Aoife, ITALSGEN Consortium, Mora, Gabriele, Calvo, Andrea, Mazzini, Letizia, Riva, Nilo, Mandrioli, Jessica, Caponnetto, Claudia, Battistini, Stefania, Volanti, Paolo, La Bella, Vincenzo, Conforti, Francesca L, Borghero, Giuseppe, Messina, Sonia, Simone, Isabella L, Trojsi, Francesca, Salvi, Fabrizio, Logullo, Francesco O, D'Alfonso, Sandra, Corrado, Lucia, Capasso, Margherita, Ferrucci, Luigi, Genomic Translation for ALS Care (GTAC) Consortium, Moreno, Cristiane de Araujo Martins, Kamalakaran, Sitharthan, Goldstein, David B, ALS Sequencing Consortium, Gitler, Aaron D, Harris, Tim, Myers, Richard M, NYGC ALS Consortium, Phatnani, Hemali, Musunuri, Rajeeva Lochan, Evani, Uday Shankar, Abhyankar, Avinash, Zody, Michael C, Answer ALS Foundation, Kaye, Julia, Finkbeiner, Steven, Wyman, Stacia K, LeNail, Alex, Lima, Leandro, Fraenkel, Ernest, Svendsen, Clive N, Thompson, Leslie M, Van Eyk, Jennifer E, Berry, James D, Miller, Timothy M, Kolb, Stephen J, Cudkowicz, Merit, Baxi, Emily, Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium, Benatar, Michael, Taylor, J Paul, Rampersaud, Evadnie, Wu, Gang, Wuu, Joanne, SLAGEN Consortium, Lauria, Giuseppe, Verde, Federico, Fogh, Isabella, Tiloca, Cinzia, Comi, Giacomo P, Sorarù, Gianni, Cereda, Cristina, French ALS Consortium, Corcia, Philippe, Laaksovirta, Hannu, Myllykangas, Liisa, Jansson, Lilja, Valori, Miko, Ealing, John, Hamdalla, Hisham, Rollinson, Sara, Pickering-Brown, Stuart, and Orrell, Richard W
Abstract: To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.
Published: 2018

19. The Library of Integrated Network-Based Cellular Signatures NIH Program: System-Level Cataloging of Human Cells Response to Perturbations.

Author: Keenan, Alexandra B, Keenan, Alexandra B, Jenkins, Sherry L, Jagodnik, Kathleen M, Koplev, Simon, He, Edward, Torre, Denis, Wang, Zichen, Dohlman, Anders B, Silverstein, Moshe C, Lachmann, Alexander, Kuleshov, Maxim V, Ma'ayan, Avi, Stathias, Vasileios, Terryn, Raymond, Cooper, Daniel, Forlin, Michele, Koleti, Amar, Vidovic, Dusica, Chung, Caty, Schürer, Stephan C, Vasiliauskas, Jouzas, Pilarczyk, Marcin, Shamsaei, Behrouz, Fazel, Mehdi, Ren, Yan, Niu, Wen, Clark, Nicholas A, White, Shana, Mahi, Naim, Zhang, Lixia, Kouril, Michal, Reichard, John F, Sivaganesan, Siva, Medvedovic, Mario, Meller, Jaroslaw, Koch, Rick J, Birtwistle, Marc R, Iyengar, Ravi, Sobie, Eric A, Azeloglu, Evren U, Kaye, Julia, Osterloh, Jeannette, Haston, Kelly, Kalra, Jaslin, Finkbiener, Steve, Li, Jonathan, Milani, Pamela, Adam, Miriam, Escalante-Chong, Renan, Sachs, Karen, Lenail, Alex, Ramamoorthy, Divya, Fraenkel, Ernest, Daigle, Gavin, Hussain, Uzma, Coye, Alyssa, Rothstein, Jeffrey, Sareen, Dhruv, Ornelas, Loren, Banuelos, Maria, Mandefro, Berhan, Ho, Ritchie, Svendsen, Clive N, Lim, Ryan G, Stocksdale, Jennifer, Casale, Malcolm S, Thompson, Terri G, Wu, Jie, Thompson, Leslie M, Dardov, Victoria, Venkatraman, Vidya, Matlock, Andrea, Van Eyk, Jennifer E, Jaffe, Jacob D, Papanastasiou, Malvina, Subramanian, Aravind, Golub, Todd R, Erickson, Sean D, Fallahi-Sichani, Mohammad, Hafner, Marc, Gray, Nathanael S, Lin, Jia-Ren, Mills, Caitlin E, Muhlich, Jeremy L, Niepel, Mario, Shamu, Caroline E, Williams, Elizabeth H, Wrobel, David, Sorger, Peter K, Heiser, Laura M, Gray, Joe W, Korkola, James E, Mills, Gordon B, LaBarge, Mark, Feiler, Heidi S, Dane, Mark A, Bucher, Elmar, Nederlof, Michel, Sudar, Damir, Gross, Sean, Keenan, Alexandra B, Keenan, Alexandra B, Jenkins, Sherry L, Jagodnik, Kathleen M, Koplev, Simon, He, Edward, Torre, Denis, Wang, Zichen, Dohlman, Anders B, Silverstein, Moshe C, Lachmann, Alexander, Kuleshov, Maxim V, Ma'ayan, Avi, Stathias, Vasileios, Terryn, Raymond, Cooper, Daniel, Forlin, Michele, Koleti, Amar, Vidovic, Dusica, Chung, Caty, Schürer, Stephan C, Vasiliauskas, Jouzas, Pilarczyk, Marcin, Shamsaei, Behrouz, Fazel, Mehdi, Ren, Yan, Niu, Wen, Clark, Nicholas A, White, Shana, Mahi, Naim, Zhang, Lixia, Kouril, Michal, Reichard, John F, Sivaganesan, Siva, Medvedovic, Mario, Meller, Jaroslaw, Koch, Rick J, Birtwistle, Marc R, Iyengar, Ravi, Sobie, Eric A, Azeloglu, Evren U, Kaye, Julia, Osterloh, Jeannette, Haston, Kelly, Kalra, Jaslin, Finkbiener, Steve, Li, Jonathan, Milani, Pamela, Adam, Miriam, Escalante-Chong, Renan, Sachs, Karen, Lenail, Alex, Ramamoorthy, Divya, Fraenkel, Ernest, Daigle, Gavin, Hussain, Uzma, Coye, Alyssa, Rothstein, Jeffrey, Sareen, Dhruv, Ornelas, Loren, Banuelos, Maria, Mandefro, Berhan, Ho, Ritchie, Svendsen, Clive N, Lim, Ryan G, Stocksdale, Jennifer, Casale, Malcolm S, Thompson, Terri G, Wu, Jie, Thompson, Leslie M, Dardov, Victoria, Venkatraman, Vidya, Matlock, Andrea, Van Eyk, Jennifer E, Jaffe, Jacob D, Papanastasiou, Malvina, Subramanian, Aravind, Golub, Todd R, Erickson, Sean D, Fallahi-Sichani, Mohammad, Hafner, Marc, Gray, Nathanael S, Lin, Jia-Ren, Mills, Caitlin E, Muhlich, Jeremy L, Niepel, Mario, Shamu, Caroline E, Williams, Elizabeth H, Wrobel, David, Sorger, Peter K, Heiser, Laura M, Gray, Joe W, Korkola, James E, Mills, Gordon B, LaBarge, Mark, Feiler, Heidi S, Dane, Mark A, Bucher, Elmar, Nederlof, Michel, Sudar, Damir, and Gross, Sean
Abstract: The Library of Integrated Network-Based Cellular Signatures (LINCS) is an NIH Common Fund program that catalogs how human cells globally respond to chemical, genetic, and disease perturbations. Resources generated by LINCS include experimental and computational methods, visualization tools, molecular and imaging data, and signatures. By assembling an integrated picture of the range of responses of human cells exposed to many perturbations, the LINCS program aims to better understand human disease and to advance the development of new therapies. Perturbations under study include drugs, genetic perturbations, tissue micro-environments, antibodies, and disease-causing mutations. Responses to perturbations are measured by transcript profiling, mass spectrometry, cell imaging, and biochemical methods, among other assays. The LINCS program focuses on cellular physiology shared among tissues and cell types relevant to an array of diseases, including cancer, heart disease, and neurodegenerative disorders. This Perspective describes LINCS technologies, datasets, tools, and approaches to data accessibility and reusability.
Published: 2018

20. Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

Author: Nicolas, A, Kenna, K, Renton, A, Ticozzi, N, Faghri, F, Chia, R, Dominov, J, Kenna, B, Nalls, M, Keagle, P, Rivera, A, van Rheenen, W, Murphy, N, van Vugt, J, Geiger, J, van der Spek, R, Pliner, H, Shankaracharya, N, Smith, B, Marangi, G, Topp, S, Abramzon, Y, Gkazi, A, Eicher, J, Kenna, A, Logullo, F, Simone, I, Logroscino, G, Salvi, F, Bartolomei, I, Borghero, G, Murru, M, Costantino, E, Pani, C, Puddu, R, Caredda, C, Piras, V, Tranquilli, S, Cuccu, S, Corongiu, D, Melis, M, Milia, A, Marrosu, F, Marrosu, M, Floris, G, Cannas, A, Capasso, M, Caponnetto, C, Mancardi, G, Origone, P, Mandich, P, Conforti, F, Cavallaro, S, Mora, G, Marinou, K, Sideri, R, Penco, S, Mosca, L, Lunetta, C, Pinter, G, Corbo, M, Riva, N, Carrera, P, Volanti, P, Mandrioli, J, Fini, N, Fasano, A, Tremolizzo, L, Arosio, A, Ferrarese, C, Trojsi, F, Tedeschi, G, Monsurrò, M, Piccirillo, G, Femiano, C, Ticca, A, Ortu, E, La Bella, V, Spataro, R, Colletti, T, Sabatelli, M, Zollino, M, Conte, A, Luigetti, M, Lattante, S, Santarelli, M, Petrucci, A, Pugliatti, M, Pirisi, A, Parish, L, Occhineri, P, Giannini, F, Battistini, S, Ricci, C, Benigni, M, Cau, T, Loi, D, Calvo, A, Moglia, C, Brunetti, M, Barberis, M, Restagno, G, Casale, F, Marrali, G, Fuda, G, Ossola, I, Cammarosano, S, Canosa, A, Ilardi, A, Manera, U, Grassano, M, Tanel, R, Pisano, F, Mazzini, L, Messina, S, D'Alfonso, S, Corrado, L, Ferrucci, L, Harms, M, Goldstein, D, Shneider, N, Goutman, S, Simmons, Z, Miller, T, Chandran, S, Pal, S, Manousakis, G, Appel, S, Simpson, E, Wang, L, Baloh, R, Gibson, S, Bedlack, R, Lacomis, D, Sareen, D, Sherman, A, Bruijn, L, Penny, M, Moreno, C, Kamalakaran, S, Allen, A, Boone, B, Brown, R, Carulli, J, Chesi, A, Chung, W, Cirulli, E, Cooper, G, Couthouis, J, Day-Williams, A, Dion, P, Gitler, A, Glass, J, Han, Y, Harris, T, Hayes, S, Jones, A, Keebler, J, Krueger, B, Lasseigne, B, Levy, S, Lu, Y, Maniatis, T, McKenna-Yasek, D, Myers, R, Petrovski, S, Pulst, S, Raphael, A, Ravits, J, Ren, Z, Rouleau, G, Sapp, P, Sims, K, Staropoli, J, Waite, L, Wang, Q, Wimbish, J, Xin, W, Phatnani, H, Kwan, J, Broach, J, Arcila-Londono, X, Lee, E, Van Deerlin, V, Fraenkel, E, Ostrow, L, Baas, F, Zaitlen, N, Berry, J, Malaspina, A, Fratta, P, Cox, G, Thompson, L, Finkbeiner, S, Dardiotis, E, Hornstein, E, Macgowan, D, Heiman-Patterson, T, Hammell, M, Patsopoulos, N, Dubnau, J, Nath, A, Musunuri, R, Evani, U, Abhyankar, A, Zody, M, Kaye, J, Wyman, S, Lenail, A, Lima, L, Rothstein, J, Svendsen, C, Van Eyk, J, Maragakis, N, Kolb, S, Cudkowicz, M, Baxi, E, Benatar, M, Taylor, J, Wu, G, Rampersaud, E, Wuu, J, Rademakers, R, Züchner, S, Schule, R, Mccauley, J, Hussain, S, Cooley, A, Wallace, M, Clayman, C, Barohn, R, Statland, J, Swenson, A, Jackson, C, Trivedi, J, Khan, S, Katz, J, Jenkins, L, Burns, T, Gwathmey, K, Caress, J, Mcmillan, C, Elman, L, Pioro, E, Heckmann, J, So, Y, Walk, D, Maiser, S, Zhang, J, Silani, V, Gellera, C, Ratti, A, Taroni, F, Lauria, G, Verde, F, Fogh, I, Tiloca, C, Comi, G, Sorarù, G, Cereda, C, De Marchi, F, Corti, S, Ceroni, M, Siciliano, G, Filosto, M, Inghilleri, M, Peverelli, S, Colombrita, C, Poletti, B, Maderna, L, Del Bo, R, Gagliardi, S, Querin, G, Bertolin, C, Pensato, V, Castellotti, B, Camu, W, Mouzat, K, Lumbroso, S, Corcia, P, Meininger, V, Besson, G, Lagrange, E, Clavelou, P, Guy, N, Couratier, P, Vourch, P, Danel, V, Bernard, E, Lemasson, G, Laaksovirta, H, Myllykangas, L, Jansson, L, Valori, M, Ealing, J, Hamdalla, H, Rollinson, S, Pickering-Brown, S, Orrell, R, Sidle, K, Hardy, J, Singleton, A, Johnson, J, Arepalli, S, Polak, M, Asress, S, Al-Sarraj, S, King, A, Troakes, C, Vance, C, de Belleroche, J, ten Asbroek, A, Muñoz-Blanco, J, Hernandez, D, Ding, J, Gibbs, J, Scholz, S, Floeter, M, Campbell, R, Landi, F, Bowser, R, Kirby, J, Pamphlett, R, Gerhard, G, Dunckley, T, Brady, C, Kowall, N, Troncoso, J, Le Ber, I, Kamel, F, Van Den Bosch, L, Strom, T, Meitinger, T, Shatunov, A, Van Eijk, K, de Carvalho, M, Kooyman, M, Middelkoop, B, Moisse, M, Mclaughlin, R, Van Es, M, Weber, M, Boylan, K, Van Blitterswijk, M, Morrison, K, Basak, A, Mora, J, Drory, V, Shaw, P, Turner, M, Talbot, K, Hardiman, O, Williams, K, Fifita, J, Nicholson, G, Blair, I, Esteban-Pérez, J, García-Redondo, A, Al-Chalabi, A, Al Kheifat, A, Andersen, P, Chio, A, Cooper-Knock, J, Dekker, A, Redondo, A, Gotkine, M, Hide, W, Iacoangeli, A, Kiernan, M, Landers, J, Mill, J, Neto, M, Pardina, J, Newhouse, S, Pinto, S, Pulit, S, Robberecht, W, Shaw, C, Sproviero, W, Tazelaar, G, van Damme, P, van den Berg, L, van Eijk, K, van Es, M, Veldink, J, Zatz, M, Bauer, D, Twine, N, Rogaeva, E, Zinman, L, Brice, A, Feldman, E, Ludolph, A, Weishaupt, J, Trojanowski, J, Stone, D, Tienari, P, Chiò, A, Traynor, B, Nicolas, Aude, Kenna, Kevin P., Renton, Alan E., Ticozzi, Nicola, Faghri, Faraz, Chia, Ruth, Dominov, Janice A., Kenna, Brendan J., Nalls, Mike A., Keagle, Pamela, Rivera, Alberto M., van Rheenen, Wouter, Murphy, Natalie A., van Vugt, Joke J. F. A., Geiger, Joshua T., van der Spek, Rick, Pliner, Hannah A., Shankaracharya, null, Smith, Bradley N., Marangi, Giuseppe, Topp, Simon D., Abramzon, Yevgeniya, Gkazi, Athina Soragia, Eicher, John D., Kenna, Aoife, Logullo, Francesco O., Simone, Isabella, Logroscino, Giancarlo, Salvi, Fabrizio, Bartolomei, Ilaria, Borghero, Giuseppe, Murru, Maria Rita, Costantino, Emanuela, Pani, Carla, Puddu, Roberta, Caredda, Carla, Piras, Valeria, Tranquilli, Stefania, Cuccu, Stefania, Corongiu, Daniela, Melis, Maurizio, Milia, Antonio, Marrosu, Francesco, Marrosu, Maria Giovanna, Floris, Gianluca, Cannas, Antonino, Capasso, Margherita, Caponnetto, Claudia, Mancardi, Gianluigi, Origone, Paola, Mandich, Paola, Conforti, Francesca L., Cavallaro, Sebastiano, Mora, Gabriele, Marinou, Kalliopi, Sideri, Riccardo, Penco, Silvana, Mosca, Lorena, Lunetta, Christian, Pinter, Giuseppe Lauria, Corbo, Massimo, Riva, Nilo, Carrera, Paola, Volanti, Paolo, Mandrioli, Jessica, Fini, Nicola, Fasano, Antonio, Tremolizzo, Lucio, Arosio, Alessandro, Ferrarese, Carlo, Trojsi, Francesca, Tedeschi, Gioacchino, Monsurrò, Maria Rosaria, Piccirillo, Giovanni, Femiano, Cinzia, Ticca, Anna, Ortu, Enzo, La Bella, Vincenzo, Spataro, Rossella, Colletti, Tiziana, Sabatelli, Mario, Zollino, Marcella, Conte, Amelia, Luigetti, Marco, Lattante, Serena, Santarelli, Marialuisa, Petrucci, Antonio, Pugliatti, Maura, Pirisi, Angelo, Parish, Leslie D., Occhineri, Patrizia, Giannini, Fabio, Battistini, Stefania, Ricci, Claudia, Benigni, Michele, Cau, Tea B., Loi, Daniela, Calvo, Andrea, Moglia, Cristina, Brunetti, Maura, Barberis, Marco, Restagno, Gabriella, Casale, Federico, Marrali, Giuseppe, Fuda, Giuseppe, Ossola, Irene, Cammarosano, Stefania, Canosa, Antonio, Ilardi, Antonio, Manera, Umberto, Grassano, Maurizio, Tanel, Raffaella, Pisano, Fabrizio, Mazzini, Letizia, Messina, Sonia, D'Alfonso, Sandra, Corrado, Lucia, Ferrucci, Luigi, Harms, Matthew B., Goldstein, David B., Shneider, Neil A., Goutman, Stephen, Simmons, Zachary, Miller, Timothy M., Chandran, Siddharthan, Pal, Suvankar, Manousakis, George, Appel, Stanley, Simpson, Ericka, Wang, Leo, Baloh, Robert H., Gibson, Summer, Bedlack, Richard S., Lacomis, David, Sareen, Dhruv, Sherman, Alexander, Bruijn, Lucie, Penny, Michelle, Moreno, Cristiane de Araujo Martins, Kamalakaran, Sitharthan, Allen, Andrew S., Boone, Braden E., Brown, Robert, Carulli, John P., Chesi, Alessandra, Chung, Wendy K., Cirulli, Elizabeth T., Cooper, Gregory M., Couthouis, Julien, Day-Williams, Aaron G., Dion, Patrick A., Gitler, Aaron D., Glass, Jonathan D., Han, Yujun, Harris, Tim, Hayes, Sebastian D., Jones, Angela L., Keebler, Jonathan, Krueger, Brian J., Lasseigne, Brittany N., Levy, Shawn E., Lu, Yi-Fan, Maniatis, Tom, McKenna-Yasek, Diane, Myers, Richard M., Petrovski, Slavé, Pulst, Stefan M., Raphael, Alya R., Ravits, John M., Ren, Zhong, Rouleau, Guy A., Sapp, Peter C., Sims, Katherine B., Staropoli, John F., Waite, Lindsay L., Wang, Quanli, Wimbish, Jack R., Xin, Winnie W., Phatnani, Hemali, Kwan, Justin, Broach, James R., Arcila-Londono, Ximena, Lee, Edward B., Van Deerlin, Vivianna M., Fraenkel, Ernest, Ostrow, Lyle W., Baas, Frank, Zaitlen, Noah, Berry, James D., Malaspina, Andrea, Fratta, Pietro, Cox, Gregory A., Thompson, Leslie M., Finkbeiner, Steven, Dardiotis, Efthimios, Hornstein, Eran, MacGowan, Daniel J., Heiman-Patterson, Terry, Hammell, Molly G., Patsopoulos, Nikolaos A., Dubnau, Joshua, Nath, Avindra, Musunuri, Rajeeva Lochan, Evani, Uday Shankar, Abhyankar, Avinash, Zody, Michael C., Kaye, Julia, Wyman, Stacia, LeNail, Alexander, Lima, Leandro, Rothstein, Jeffrey D., Svendsen, Clive N., Van Eyk, Jenny, Maragakis, Nicholas J., Kolb, Stephen J., Cudkowicz, Merit, Baxi, Emily, Wyman, Stacia K., Van Eyk, Jennifer E., Benatar, Michael, Taylor, J. Paul, Wu, Gang, Rampersaud, Evadnie, Wuu, Joanne, Rademakers, Rosa, Züchner, Stephan, Schule, Rebecca, McCauley, Jacob, Hussain, Sumaira, Cooley, Anne, Wallace, Marielle, Clayman, Christine, Barohn, Richard, Statland, Jeffrey, Ravits, John, Swenson, Andrea, Jackson, Carlayne, Trivedi, Jaya, Khan, Shaida, Katz, Jonathan, Jenkins, Liberty, Burns, Ted, Gwathmey, Kelly, Caress, James, McMillan, Corey, Elman, Lauren, Pioro, Erik, Heckmann, Jeannine, So, Yuen, Walk, David, Maiser, Samuel, Zhang, Jinghui, Silani, Vincenzo, Gellera, Cinzia, Ratti, Antonia, Taroni, Franco, Lauria, Giuseppe, Verde, Federico, Fogh, Isabella, Tiloca, Cinzia, Comi, Giacomo P., Sorarù, Gianni, Cereda, Cristina, De Marchi, Fabiola, Corti, Stefania, Ceroni, Mauro, Siciliano, Gabriele, Filosto, Massimiliano, Inghilleri, Maurizio, Peverelli, Silvia, Colombrita, Claudia, Poletti, Barbara, Maderna, Luca, Del Bo, Roberto, Gagliardi, Stella, Querin, Giorgia, Bertolin, Cinzia, Pensato, Viviana, Castellotti, Barbara, Camu, William, Mouzat, Kevin, Lumbroso, Serge, Corcia, Philippe, Meininger, Vincent, Besson, Gérard, Lagrange, Emmeline, Clavelou, Pierre, Guy, Nathalie, Couratier, Philippe, Vourch, Patrick, Danel, Véronique, Bernard, Emilien, Lemasson, Gwendal, Laaksovirta, Hannu, Myllykangas, Liisa, Jansson, Lilja, Valori, Miko, Ealing, John, Hamdalla, Hisham, Rollinson, Sara, Pickering-Brown, Stuart, Orrell, Richard W., Sidle, Katie C., Hardy, John, Singleton, Andrew B., Johnson, Janel O., Arepalli, Sampath, Polak, Meraida, Asress, Seneshaw, Al-Sarraj, Safa, King, Andrew, Troakes, Claire, Vance, Caroline, de Belleroche, Jacqueline, ten Asbroek, Anneloor L. M. A., Muñoz-Blanco, José Luis, Hernandez, Dena G., Ding, Jinhui, Gibbs, J. Raphael, Scholz, Sonja W., Floeter, Mary Kay, Campbell, Roy H., Landi, Francesco, Bowser, Robert, MacGowan, Daniel J. L., Kirby, Janine, Pioro, Erik P., Pamphlett, Roger, Broach, James, Gerhard, Glenn, Dunckley, Travis L., Brady, Christopher B., Kowall, Neil W., Troncoso, Juan C., Le Ber, Isabelle, Heiman-Patterson, Terry D., Kamel, Freya, Van Den Bosch, Ludo, Strom, Tim M., Meitinger, Thomas, Shatunov, Aleksey, Van Eijk, Kristel R., de Carvalho, Mamede, Kooyman, Maarten, Middelkoop, Bas, Moisse, Mattieu, McLaughlin, Russell L., Van Es, Michael A., Weber, Markus, Boylan, Kevin B., Van Blitterswijk, Marka, Morrison, Karen E., Basak, A. Nazli, Mora, Jesús S., Drory, Vivian E., Shaw, Pamela J., Turner, Martin R., Talbot, Kevin, Hardiman, Orla, Williams, Kelly L., Fifita, Jennifer A., Nicholson, Garth A., Blair, Ian P., Esteban-Pérez, Jesús, García-Redondo, Alberto, Al-Chalabi, Ammar, Al Kheifat, Ahmad, Andersen, Peter, Chio, Adriano, Cooper-Knock, Jonathan, Dekker, Annelot, Drory, Vivian, Redondo, Alberto Garcia, Gotkine, Marc, Hide, Winston, Iacoangeli, Alfredo, Glass, Jonathan, Kenna, Kevin, Kiernan, Matthew, Landers, John, McLaughlin, Russell, Mill, Jonathan, Neto, Miguel Mitne, Pardina, Jesus Mora, Morrison, Karen, Newhouse, Stephen, Pinto, Susana, Pulit, Sara, Robberecht, Wim, Shaw, Pamela, Shaw, Chris, Sproviero, William, Tazelaar, Gijs, van Damme, Philip, van den Berg, Leonard, van Eijk, Kristel, van Es, Michael, van Vugt, Joke, Veldink, Jan, Zatz, Mayana, Bauer, Denis C., Twine, Natalie A., Rogaeva, Ekaterina, Zinman, Lorne, Brice, Alexis, Goutman, Stephen A., Feldman, Eva L., Gibson, Summer B., Ludolph, Albert C., Andersen, Peter M., Weishaupt, Jochen H., Trojanowski, John Q., Brown, Robert H., van den Berg, Leonard H., Veldink, Jan H., Stone, David J., Tienari, Pentti, Chiò, Adriano, Shaw, Christopher E., Traynor, Bryan J., Landers, John E., Nicolas, A, Kenna, K, Renton, A, Ticozzi, N, Faghri, F, Chia, R, Dominov, J, Kenna, B, Nalls, M, Keagle, P, Rivera, A, van Rheenen, W, Murphy, N, van Vugt, J, Geiger, J, van der Spek, R, Pliner, H, Shankaracharya, N, Smith, B, Marangi, G, Topp, S, Abramzon, Y, Gkazi, A, Eicher, J, Kenna, A, Logullo, F, Simone, I, Logroscino, G, Salvi, F, Bartolomei, I, Borghero, G, Murru, M, Costantino, E, Pani, C, Puddu, R, Caredda, C, Piras, V, Tranquilli, S, Cuccu, S, Corongiu, D, Melis, M, Milia, A, Marrosu, F, Marrosu, M, Floris, G, Cannas, A, Capasso, M, Caponnetto, C, Mancardi, G, Origone, P, Mandich, P, Conforti, F, Cavallaro, S, Mora, G, Marinou, K, Sideri, R, Penco, S, Mosca, L, Lunetta, C, Pinter, G, Corbo, M, Riva, N, Carrera, P, Volanti, P, Mandrioli, J, Fini, N, Fasano, A, Tremolizzo, L, Arosio, A, Ferrarese, C, Trojsi, F, Tedeschi, G, Monsurrò, M, Piccirillo, G, Femiano, C, Ticca, A, Ortu, E, La Bella, V, Spataro, R, Colletti, T, Sabatelli, M, Zollino, M, Conte, A, Luigetti, M, Lattante, S, Santarelli, M, Petrucci, A, Pugliatti, M, Pirisi, A, Parish, L, Occhineri, P, Giannini, F, Battistini, S, Ricci, C, Benigni, M, Cau, T, Loi, D, Calvo, A, Moglia, C, Brunetti, M, Barberis, M, Restagno, G, Casale, F, Marrali, G, Fuda, G, Ossola, I, Cammarosano, S, Canosa, A, Ilardi, A, Manera, U, Grassano, M, Tanel, R, Pisano, F, Mazzini, L, Messina, S, D'Alfonso, S, Corrado, L, Ferrucci, L, Harms, M, Goldstein, D, Shneider, N, Goutman, S, Simmons, Z, Miller, T, Chandran, S, Pal, S, Manousakis, G, Appel, S, Simpson, E, Wang, L, Baloh, R, Gibson, S, Bedlack, R, Lacomis, D, Sareen, D, Sherman, A, Bruijn, L, Penny, M, Moreno, C, Kamalakaran, S, Allen, A, Boone, B, Brown, R, Carulli, J, Chesi, A, Chung, W, Cirulli, E, Cooper, G, Couthouis, J, Day-Williams, A, Dion, P, Gitler, A, Glass, J, Han, Y, Harris, T, Hayes, S, Jones, A, Keebler, J, Krueger, B, Lasseigne, B, Levy, S, Lu, Y, Maniatis, T, McKenna-Yasek, D, Myers, R, Petrovski, S, Pulst, S, Raphael, A, Ravits, J, Ren, Z, Rouleau, G, Sapp, P, Sims, K, Staropoli, J, Waite, L, Wang, Q, Wimbish, J, Xin, W, Phatnani, H, Kwan, J, Broach, J, Arcila-Londono, X, Lee, E, Van Deerlin, V, Fraenkel, E, Ostrow, L, Baas, F, Zaitlen, N, Berry, J, Malaspina, A, Fratta, P, Cox, G, Thompson, L, Finkbeiner, S, Dardiotis, E, Hornstein, E, Macgowan, D, Heiman-Patterson, T, Hammell, M, Patsopoulos, N, Dubnau, J, Nath, A, Musunuri, R, Evani, U, Abhyankar, A, Zody, M, Kaye, J, Wyman, S, Lenail, A, Lima, L, Rothstein, J, Svendsen, C, Van Eyk, J, Maragakis, N, Kolb, S, Cudkowicz, M, Baxi, E, Benatar, M, Taylor, J, Wu, G, Rampersaud, E, Wuu, J, Rademakers, R, Züchner, S, Schule, R, Mccauley, J, Hussain, S, Cooley, A, Wallace, M, Clayman, C, Barohn, R, Statland, J, Swenson, A, Jackson, C, Trivedi, J, Khan, S, Katz, J, Jenkins, L, Burns, T, Gwathmey, K, Caress, J, Mcmillan, C, Elman, L, Pioro, E, Heckmann, J, So, Y, Walk, D, Maiser, S, Zhang, J, Silani, V, Gellera, C, Ratti, A, Taroni, F, Lauria, G, Verde, F, Fogh, I, Tiloca, C, Comi, G, Sorarù, G, Cereda, C, De Marchi, F, Corti, S, Ceroni, M, Siciliano, G, Filosto, M, Inghilleri, M, Peverelli, S, Colombrita, C, Poletti, B, Maderna, L, Del Bo, R, Gagliardi, S, Querin, G, Bertolin, C, Pensato, V, Castellotti, B, Camu, W, Mouzat, K, Lumbroso, S, Corcia, P, Meininger, V, Besson, G, Lagrange, E, Clavelou, P, Guy, N, Couratier, P, Vourch, P, Danel, V, Bernard, E, Lemasson, G, Laaksovirta, H, Myllykangas, L, Jansson, L, Valori, M, Ealing, J, Hamdalla, H, Rollinson, S, Pickering-Brown, S, Orrell, R, Sidle, K, Hardy, J, Singleton, A, Johnson, J, Arepalli, S, Polak, M, Asress, S, Al-Sarraj, S, King, A, Troakes, C, Vance, C, de Belleroche, J, ten Asbroek, A, Muñoz-Blanco, J, Hernandez, D, Ding, J, Gibbs, J, Scholz, S, Floeter, M, Campbell, R, Landi, F, Bowser, R, Kirby, J, Pamphlett, R, Gerhard, G, Dunckley, T, Brady, C, Kowall, N, Troncoso, J, Le Ber, I, Kamel, F, Van Den Bosch, L, Strom, T, Meitinger, T, Shatunov, A, Van Eijk, K, de Carvalho, M, Kooyman, M, Middelkoop, B, Moisse, M, Mclaughlin, R, Van Es, M, Weber, M, Boylan, K, Van Blitterswijk, M, Morrison, K, Basak, A, Mora, J, Drory, V, Shaw, P, Turner, M, Talbot, K, Hardiman, O, Williams, K, Fifita, J, Nicholson, G, Blair, I, Esteban-Pérez, J, García-Redondo, A, Al-Chalabi, A, Al Kheifat, A, Andersen, P, Chio, A, Cooper-Knock, J, Dekker, A, Redondo, A, Gotkine, M, Hide, W, Iacoangeli, A, Kiernan, M, Landers, J, Mill, J, Neto, M, Pardina, J, Newhouse, S, Pinto, S, Pulit, S, Robberecht, W, Shaw, C, Sproviero, W, Tazelaar, G, van Damme, P, van den Berg, L, van Eijk, K, van Es, M, Veldink, J, Zatz, M, Bauer, D, Twine, N, Rogaeva, E, Zinman, L, Brice, A, Feldman, E, Ludolph, A, Weishaupt, J, Trojanowski, J, Stone, D, Tienari, P, Chiò, A, Traynor, B, Nicolas, Aude, Kenna, Kevin P., Renton, Alan E., Ticozzi, Nicola, Faghri, Faraz, Chia, Ruth, Dominov, Janice A., Kenna, Brendan J., Nalls, Mike A., Keagle, Pamela, Rivera, Alberto M., van Rheenen, Wouter, Murphy, Natalie A., van Vugt, Joke J. F. A., Geiger, Joshua T., van der Spek, Rick, Pliner, Hannah A., Shankaracharya, null, Smith, Bradley N., Marangi, Giuseppe, Topp, Simon D., Abramzon, Yevgeniya, Gkazi, Athina Soragia, Eicher, John D., Kenna, Aoife, Logullo, Francesco O., Simone, Isabella, Logroscino, Giancarlo, Salvi, Fabrizio, Bartolomei, Ilaria, Borghero, Giuseppe, Murru, Maria Rita, Costantino, Emanuela, Pani, Carla, Puddu, Roberta, Caredda, Carla, Piras, Valeria, Tranquilli, Stefania, Cuccu, Stefania, Corongiu, Daniela, Melis, Maurizio, Milia, Antonio, Marrosu, Francesco, Marrosu, Maria Giovanna, Floris, Gianluca, Cannas, Antonino, Capasso, Margherita, Caponnetto, Claudia, Mancardi, Gianluigi, Origone, Paola, Mandich, Paola, Conforti, Francesca L., Cavallaro, Sebastiano, Mora, Gabriele, Marinou, Kalliopi, Sideri, Riccardo, Penco, Silvana, Mosca, Lorena, Lunetta, Christian, Pinter, Giuseppe Lauria, Corbo, Massimo, Riva, Nilo, Carrera, Paola, Volanti, Paolo, Mandrioli, Jessica, Fini, Nicola, Fasano, Antonio, Tremolizzo, Lucio, Arosio, Alessandro, Ferrarese, Carlo, Trojsi, Francesca, Tedeschi, Gioacchino, Monsurrò, Maria Rosaria, Piccirillo, Giovanni, Femiano, Cinzia, Ticca, Anna, Ortu, Enzo, La Bella, Vincenzo, Spataro, Rossella, Colletti, Tiziana, Sabatelli, Mario, Zollino, Marcella, Conte, Amelia, Luigetti, Marco, Lattante, Serena, Santarelli, Marialuisa, Petrucci, Antonio, Pugliatti, Maura, Pirisi, Angelo, Parish, Leslie D., Occhineri, Patrizia, Giannini, Fabio, Battistini, Stefania, Ricci, Claudia, Benigni, Michele, Cau, Tea B., Loi, Daniela, Calvo, Andrea, Moglia, Cristina, Brunetti, Maura, Barberis, Marco, Restagno, Gabriella, Casale, Federico, Marrali, Giuseppe, Fuda, Giuseppe, Ossola, Irene, Cammarosano, Stefania, Canosa, Antonio, Ilardi, Antonio, Manera, Umberto, Grassano, Maurizio, Tanel, Raffaella, Pisano, Fabrizio, Mazzini, Letizia, Messina, Sonia, D'Alfonso, Sandra, Corrado, Lucia, Ferrucci, Luigi, Harms, Matthew B., Goldstein, David B., Shneider, Neil A., Goutman, Stephen, Simmons, Zachary, Miller, Timothy M., Chandran, Siddharthan, Pal, Suvankar, Manousakis, George, Appel, Stanley, Simpson, Ericka, Wang, Leo, Baloh, Robert H., Gibson, Summer, Bedlack, Richard S., Lacomis, David, Sareen, Dhruv, Sherman, Alexander, Bruijn, Lucie, Penny, Michelle, Moreno, Cristiane de Araujo Martins, Kamalakaran, Sitharthan, Allen, Andrew S., Boone, Braden E., Brown, Robert, Carulli, John P., Chesi, Alessandra, Chung, Wendy K., Cirulli, Elizabeth T., Cooper, Gregory M., Couthouis, Julien, Day-Williams, Aaron G., Dion, Patrick A., Gitler, Aaron D., Glass, Jonathan D., Han, Yujun, Harris, Tim, Hayes, Sebastian D., Jones, Angela L., Keebler, Jonathan, Krueger, Brian J., Lasseigne, Brittany N., Levy, Shawn E., Lu, Yi-Fan, Maniatis, Tom, McKenna-Yasek, Diane, Myers, Richard M., Petrovski, Slavé, Pulst, Stefan M., Raphael, Alya R., Ravits, John M., Ren, Zhong, Rouleau, Guy A., Sapp, Peter C., Sims, Katherine B., Staropoli, John F., Waite, Lindsay L., Wang, Quanli, Wimbish, Jack R., Xin, Winnie W., Phatnani, Hemali, Kwan, Justin, Broach, James R., Arcila-Londono, Ximena, Lee, Edward B., Van Deerlin, Vivianna M., Fraenkel, Ernest, Ostrow, Lyle W., Baas, Frank, Zaitlen, Noah, Berry, James D., Malaspina, Andrea, Fratta, Pietro, Cox, Gregory A., Thompson, Leslie M., Finkbeiner, Steven, Dardiotis, Efthimios, Hornstein, Eran, MacGowan, Daniel J., Heiman-Patterson, Terry, Hammell, Molly G., Patsopoulos, Nikolaos A., Dubnau, Joshua, Nath, Avindra, Musunuri, Rajeeva Lochan, Evani, Uday Shankar, Abhyankar, Avinash, Zody, Michael C., Kaye, Julia, Wyman, Stacia, LeNail, Alexander, Lima, Leandro, Rothstein, Jeffrey D., Svendsen, Clive N., Van Eyk, Jenny, Maragakis, Nicholas J., Kolb, Stephen J., Cudkowicz, Merit, Baxi, Emily, Wyman, Stacia K., Van Eyk, Jennifer E., Benatar, Michael, Taylor, J. Paul, Wu, Gang, Rampersaud, Evadnie, Wuu, Joanne, Rademakers, Rosa, Züchner, Stephan, Schule, Rebecca, McCauley, Jacob, Hussain, Sumaira, Cooley, Anne, Wallace, Marielle, Clayman, Christine, Barohn, Richard, Statland, Jeffrey, Ravits, John, Swenson, Andrea, Jackson, Carlayne, Trivedi, Jaya, Khan, Shaida, Katz, Jonathan, Jenkins, Liberty, Burns, Ted, Gwathmey, Kelly, Caress, James, McMillan, Corey, Elman, Lauren, Pioro, Erik, Heckmann, Jeannine, So, Yuen, Walk, David, Maiser, Samuel, Zhang, Jinghui, Silani, Vincenzo, Gellera, Cinzia, Ratti, Antonia, Taroni, Franco, Lauria, Giuseppe, Verde, Federico, Fogh, Isabella, Tiloca, Cinzia, Comi, Giacomo P., Sorarù, Gianni, Cereda, Cristina, De Marchi, Fabiola, Corti, Stefania, Ceroni, Mauro, Siciliano, Gabriele, Filosto, Massimiliano, Inghilleri, Maurizio, Peverelli, Silvia, Colombrita, Claudia, Poletti, Barbara, Maderna, Luca, Del Bo, Roberto, Gagliardi, Stella, Querin, Giorgia, Bertolin, Cinzia, Pensato, Viviana, Castellotti, Barbara, Camu, William, Mouzat, Kevin, Lumbroso, Serge, Corcia, Philippe, Meininger, Vincent, Besson, Gérard, Lagrange, Emmeline, Clavelou, Pierre, Guy, Nathalie, Couratier, Philippe, Vourch, Patrick, Danel, Véronique, Bernard, Emilien, Lemasson, Gwendal, Laaksovirta, Hannu, Myllykangas, Liisa, Jansson, Lilja, Valori, Miko, Ealing, John, Hamdalla, Hisham, Rollinson, Sara, Pickering-Brown, Stuart, Orrell, Richard W., Sidle, Katie C., Hardy, John, Singleton, Andrew B., Johnson, Janel O., Arepalli, Sampath, Polak, Meraida, Asress, Seneshaw, Al-Sarraj, Safa, King, Andrew, Troakes, Claire, Vance, Caroline, de Belleroche, Jacqueline, ten Asbroek, Anneloor L. M. A., Muñoz-Blanco, José Luis, Hernandez, Dena G., Ding, Jinhui, Gibbs, J. Raphael, Scholz, Sonja W., Floeter, Mary Kay, Campbell, Roy H., Landi, Francesco, Bowser, Robert, MacGowan, Daniel J. L., Kirby, Janine, Pioro, Erik P., Pamphlett, Roger, Broach, James, Gerhard, Glenn, Dunckley, Travis L., Brady, Christopher B., Kowall, Neil W., Troncoso, Juan C., Le Ber, Isabelle, Heiman-Patterson, Terry D., Kamel, Freya, Van Den Bosch, Ludo, Strom, Tim M., Meitinger, Thomas, Shatunov, Aleksey, Van Eijk, Kristel R., de Carvalho, Mamede, Kooyman, Maarten, Middelkoop, Bas, Moisse, Mattieu, McLaughlin, Russell L., Van Es, Michael A., Weber, Markus, Boylan, Kevin B., Van Blitterswijk, Marka, Morrison, Karen E., Basak, A. Nazli, Mora, Jesús S., Drory, Vivian E., Shaw, Pamela J., Turner, Martin R., Talbot, Kevin, Hardiman, Orla, Williams, Kelly L., Fifita, Jennifer A., Nicholson, Garth A., Blair, Ian P., Esteban-Pérez, Jesús, García-Redondo, Alberto, Al-Chalabi, Ammar, Al Kheifat, Ahmad, Andersen, Peter, Chio, Adriano, Cooper-Knock, Jonathan, Dekker, Annelot, Drory, Vivian, Redondo, Alberto Garcia, Gotkine, Marc, Hide, Winston, Iacoangeli, Alfredo, Glass, Jonathan, Kenna, Kevin, Kiernan, Matthew, Landers, John, McLaughlin, Russell, Mill, Jonathan, Neto, Miguel Mitne, Pardina, Jesus Mora, Morrison, Karen, Newhouse, Stephen, Pinto, Susana, Pulit, Sara, Robberecht, Wim, Shaw, Pamela, Shaw, Chris, Sproviero, William, Tazelaar, Gijs, van Damme, Philip, van den Berg, Leonard, van Eijk, Kristel, van Es, Michael, van Vugt, Joke, Veldink, Jan, Zatz, Mayana, Bauer, Denis C., Twine, Natalie A., Rogaeva, Ekaterina, Zinman, Lorne, Brice, Alexis, Goutman, Stephen A., Feldman, Eva L., Gibson, Summer B., Ludolph, Albert C., Andersen, Peter M., Weishaupt, Jochen H., Trojanowski, John Q., Brown, Robert H., van den Berg, Leonard H., Veldink, Jan H., Stone, David J., Tienari, Pentti, Chiò, Adriano, Shaw, Christopher E., Traynor, Bryan J., and Landers, John E.
Abstract: To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS. Using a large-scale genome-wide association study and exome sequencing, we identified KIF5A as a novel gene associated with ALS. Our data broaden the phenotype resulting from mutations in KIF5A and highlight the importance of cytoskeletal defects in the pathogenesis of ALS.
Published: 2018

21. Report of the international conference on manufacturing and testing of pluripotent stem cells

Author: Abbot, Stewart, Agbanyo, Francisca, Ahlfors, Jan-Eric, Baghbaderani, Behnam A., Bartido, Shirley, Bharti, Kapil, Burke, Carl, Carlsson, Bjorn, Cavagnaro, Joy, Creasey, Abla, Lin, Stephen, DiGiusto, David, Francissen, Kathy, Gaffney, Andrew, Goldring, Christopher, Gorba, Thorsten, Griffiths, Elwyn, Lubiniecki, Anthony, Vandeputte, Joris, Hanatani, Tadaaki, Hayakawa, Takao, Heki, Tatsuo, Hoogendoorn, Karin, Kawamata, Shin, Kimura, Hironobu, Kirkeby, Agnete, Knezevic, Ivana, Lebkowski, Jane, Lin-Gibson, Shen, O'Shea, Orla, Pera, Martin, Petricciani, John, Pigeau, Gary, Ratcliffe, Anthony, Sato, Yoji, Schumann, Gerald G., Shingleton, William, Stacey, Chair Glyn, Sullivan, Stephen, Svendsen, Clive N., Trouvin, Jean-Hugues, Yuan, Bao-Zhu, Zoon, Kathryn, Abbot, Stewart, Agbanyo, Francisca, Ahlfors, Jan-Eric, Baghbaderani, Behnam A., Bartido, Shirley, Bharti, Kapil, Burke, Carl, Carlsson, Bjorn, Cavagnaro, Joy, Creasey, Abla, Lin, Stephen, DiGiusto, David, Francissen, Kathy, Gaffney, Andrew, Goldring, Christopher, Gorba, Thorsten, Griffiths, Elwyn, Lubiniecki, Anthony, Vandeputte, Joris, Hanatani, Tadaaki, Hayakawa, Takao, Heki, Tatsuo, Hoogendoorn, Karin, Kawamata, Shin, Kimura, Hironobu, Kirkeby, Agnete, Knezevic, Ivana, Lebkowski, Jane, Lin-Gibson, Shen, O'Shea, Orla, Pera, Martin, Petricciani, John, Pigeau, Gary, Ratcliffe, Anthony, Sato, Yoji, Schumann, Gerald G., Shingleton, William, Stacey, Chair Glyn, Sullivan, Stephen, Svendsen, Clive N., Trouvin, Jean-Hugues, Yuan, Bao-Zhu, and Zoon, Kathryn
Abstract: Sessions included an overview of past cell therapy (CT) conferences sponsored by the International Alliance for Biological Standardization (IABS). The sessions highlighted challenges in the field of human pluripotent stem cells (hPSCs) and also addressed specific points on manufacturing, bioanalytics and comparability, tumorigenicity testing, storage, and shipping. Panel discussions complemented the presentations. The conference concluded that a range of new standardization groups is emerging that could help the field, but ways must be found to ensure that these efforts are coordinated. In addition, there are opportunities for regulatory convergence starting with a gap analysis of existing guidelines to determine what might be missing and what issues might be creating divergence. More specific global regulatory guidance, preferably from WHO, would be welcome. IABS and the California Institute for Regenerative Medicine (CIRM) will explore with stakeholders the development of a practical and innovative road map to support early CT product (CTP) developers.[on SciFinder (R)]
Published: 2018

22. Developmental alterations in Huntington's disease neural cells and pharmacological rescue in cells and mice

Author: Massachusetts Institute of Technology. Department of Biological Engineering, Massachusetts Institute of Technology. Department of Biology, Koch Institute for Integrative Cancer Research at MIT, Kedaigle, Amanda Joy, Wasylenko, Theresa Anne, Yildirim, Ferah, Ng, Christopher W., Milani, Pamela, Housman, David E, Fraenkel, Ernest, HD iPSC Consortium, Lim, Ryan G, Salazar, Lisa L, Wilton, Daniel K, King, Alvin R, Stocksdale, Jennifer T, Sharifabad, Delaram, Lau, L Alice, Stevens, Beth, Reidling, Jack C, Winokur, Sara T, Casale, Malcolm S, Thompson, Leslie M, Pardo, Mónica, Díaz-Barriga, A Gerardo García, Straccia, Marco, Sanders, Phil, Alberch, Jordi, Canals, Josep M, Kaye, Julia A, Dunlap, Mariah, Jo, Lisa, May, Hanna, Mount, Elliot, Anderson-Bergman, Cliff, Haston, Kelly, Finkbeiner, Steven, Allen, Nicholas D, Kemp, Paul J, Atwal, Ranjit Singh, Biagioli, Marta, Gusella, James F, MacDonald, Marcy E, Akimov, Sergey S, Arbez, Nicolas, Stewart, Jacqueline, Ross, Christopher A, Mattis, Virginia B, Tom, Colton M, Ornelas, Loren, Sahabian, Anais, Lenaeus, Lindsay, Mandefro, Berhan, Sareen, Dhruv, Svendsen, Clive N, Massachusetts Institute of Technology. Department of Biological Engineering, Massachusetts Institute of Technology. Department of Biology, Koch Institute for Integrative Cancer Research at MIT, Kedaigle, Amanda Joy, Wasylenko, Theresa Anne, Yildirim, Ferah, Ng, Christopher W., Milani, Pamela, Housman, David E, Fraenkel, Ernest, HD iPSC Consortium, Lim, Ryan G, Salazar, Lisa L, Wilton, Daniel K, King, Alvin R, Stocksdale, Jennifer T, Sharifabad, Delaram, Lau, L Alice, Stevens, Beth, Reidling, Jack C, Winokur, Sara T, Casale, Malcolm S, Thompson, Leslie M, Pardo, Mónica, Díaz-Barriga, A Gerardo García, Straccia, Marco, Sanders, Phil, Alberch, Jordi, Canals, Josep M, Kaye, Julia A, Dunlap, Mariah, Jo, Lisa, May, Hanna, Mount, Elliot, Anderson-Bergman, Cliff, Haston, Kelly, Finkbeiner, Steven, Allen, Nicholas D, Kemp, Paul J, Atwal, Ranjit Singh, Biagioli, Marta, Gusella, James F, MacDonald, Marcy E, Akimov, Sergey S, Arbez, Nicolas, Stewart, Jacqueline, Ross, Christopher A, Mattis, Virginia B, Tom, Colton M, Ornelas, Loren, Sahabian, Anais, Lenaeus, Lindsay, Mandefro, Berhan, Sareen, Dhruv, and Svendsen, Clive N
Abstract: Neural cultures derived from Huntington's disease (HD) patient-derived induced pluripotent stem cells were used for 'omics' analyses to identify mechanisms underlying neurodegeneration. RNA-seq analysis identified genes in glutamate and GABA signaling, axonal guidance and calcium influx whose expression was decreased in HD cultures. One-third of gene changes were in pathways regulating neuronal development and maturation. When mapped to stages of mouse striatal development, the profiles aligned with earlier embryonic stages of neuronal differentiation. We observed a strong correlation between HD-related histone marks, gene expression and unique peak profiles associated with dysregulated genes, suggesting a coordinated epigenetic program. Treatment with isoxazole-9, which targets key dysregulated pathways, led to amelioration of expanded polyglutamine repeat-associated phenotypes in neural cells and of cognitive impairment and synaptic pathology in HD model R6/2 mice. These data suggest that mutant huntingtin impairs neurodevelopmental pathways that could disrupt synaptic homeostasis and increase vulnerability to the pathologic consequence of expanded polyglutamine repeats over time., National Institutes of Health (U.S.) (Grant U54 NS091046), National Institutes of Health (U.S.) (Grant NS089076), National Institutes of Health (U.S.) (Grant R01GM089903)
Published: 2018

23. Directed Differentiation of Human Induced Pluripotent Stem Cells into Fallopian Tube Epithelium.

Author: Yucer, Nur, Yucer, Nur, Holzapfel, Marie, Jenkins Vogel, Tilley, Lenaeus, Lindsay, Ornelas, Loren, Laury, Anna, Sareen, Dhruv, Barrett, Robert, Karlan, Beth Y, Svendsen, Clive N, Yucer, Nur, Yucer, Nur, Holzapfel, Marie, Jenkins Vogel, Tilley, Lenaeus, Lindsay, Ornelas, Loren, Laury, Anna, Sareen, Dhruv, Barrett, Robert, Karlan, Beth Y, and Svendsen, Clive N
Abstract: The fallopian tube epithelium (FTE) has been recognized as a site of origin of high-grade serous ovarian cancer (HGSC). However, the absence of relevant in vitro human models that can recapitulate tissue-specific architecture has hindered our understanding of FTE transformation and initiation of HGSC. Here, induced pluripotent stem cells (iPSCs) were used to establish a novel 3-dimensional (3D) human FTE organoid in vitro model containing the relevant cell types of the human fallopian tube as well as a luminal architecture that closely reflects the organization of fallopian tissues in vivo. Modulation of Wnt and BMP signaling directed iPSC differentiation into Müllerian cells and subsequent use of pro-Müllerian growth factors promoted FTE precursors. The expression and localization of Müllerian markers verified correct cellular differentiation. An innovative 3D growth platform, which enabled the FTE organoid to self-organize into a convoluted luminal structure, permitted matured differentiation to a FTE lineage. This powerful human-derived FTE organoid model can be used to study the earliest stages of HGSC development and to identify novel and specific biomarkers of early fallopian tube epithelial cell transformation.
Published: 2017

24. Huntington's Disease iPSC-Derived Brain Microvascular Endothelial Cells Reveal WNT-Mediated Angiogenic and Blood-Brain Barrier Deficits.

Author: Lim, Ryan G, Lim, Ryan G, Quan, Chris, Reyes-Ortiz, Andrea M, Lutz, Sarah E, Kedaigle, Amanda J, Gipson, Theresa A, Wu, Jie, Vatine, Gad D, Stocksdale, Jennifer, Casale, Malcolm S, Svendsen, Clive N, Fraenkel, Ernest, Housman, David E, Agalliu, Dritan, Thompson, Leslie M, Lim, Ryan G, Lim, Ryan G, Quan, Chris, Reyes-Ortiz, Andrea M, Lutz, Sarah E, Kedaigle, Amanda J, Gipson, Theresa A, Wu, Jie, Vatine, Gad D, Stocksdale, Jennifer, Casale, Malcolm S, Svendsen, Clive N, Fraenkel, Ernest, Housman, David E, Agalliu, Dritan, and Thompson, Leslie M
Abstract: Brain microvascular endothelial cells (BMECs) are an essential component of the blood-brain barrier (BBB) that shields the brain against toxins and immune cells. While BBB dysfunction exists in neurological disorders, including Huntington's disease (HD), it is not known if BMECs themselves are functionally compromised to promote BBB dysfunction. Further, the underlying mechanisms of BBB dysfunction remain elusive given limitations with mouse models and post-mortem tissue to identify primary deficits. We undertook a transcriptome and functional analysis of human induced pluripotent stem cell (iPSC)-derived BMECs (iBMEC) from HD patients or unaffected controls. We demonstrate that HD iBMECs have intrinsic abnormalities in angiogenesis and barrier properties, as well as in signaling pathways governing these processes. Thus, our findings provide an iPSC-derived BBB model for a neurodegenerative disease and demonstrate autonomous neurovascular deficits that may underlie HD pathology with implications for therapeutics and drug delivery.
Published: 2017

25. Patients with ALS show highly correlated progression rates in left and right limb muscles.

Author: Rushton, David J, Rushton, David J, Andres, Patricia L, Allred, Peggy, Baloh, Robert H, Svendsen, Clive N, Rushton, David J, Rushton, David J, Andres, Patricia L, Allred, Peggy, Baloh, Robert H, and Svendsen, Clive N
Abstract: ObjectiveAmyotrophic lateral sclerosis (ALS) progresses at different rates between patients, making clinical trial design difficult and dependent on large cohorts of patients. Currently, there are few data showing whether the left and right limbs progress at the same or different rates. This study addresses rates of decline in specific muscle groups of patients with ALS and assesses whether there is a relationship between left and right muscles in the same patient, regardless of overall progression.MethodsA large cohort of patients was used to assess decline in muscle strength in right and left limbs over time using 2 different methods: The Tufts Quantitative Neuromuscular Exam and Accurate Test of Limb Isometric Strength protocol. Then advanced linear regression statistical methods were applied to assess progression rates in each limb.ResultsThis report shows that linearized progression models can predict general slopes of decline with good accuracy. Critically, the data demonstrate that while overall decline is variable, there is a high degree of correlation between left and right muscle decline in ALS. This implies that irrespective of which muscle starts declining soonest or latest, their rates of decline following onset are more consistent.ConclusionsFirst, this study demonstrates a high degree of power when using unilateral treatment approaches to detect a slowing in disease progression in smaller groups of patients, thus allowing for paired statistical tests. These findings will be useful in transplantation trials that use muscle decline to track disease progression in ALS. Second, these findings discuss methods, such as tactical selection of muscle groups, which can improve the power efficiency of all ALS clinical trials.
Published: 2017

26. Patients with ALS show highly correlated progression rates in left and right limb muscles.

Author: Rushton, David J, Rushton, David J, Andres, Patricia L, Allred, Peggy, Baloh, Robert H, Svendsen, Clive N, Rushton, David J, Rushton, David J, Andres, Patricia L, Allred, Peggy, Baloh, Robert H, and Svendsen, Clive N
Abstract: ObjectiveAmyotrophic lateral sclerosis (ALS) progresses at different rates between patients, making clinical trial design difficult and dependent on large cohorts of patients. Currently, there are few data showing whether the left and right limbs progress at the same or different rates. This study addresses rates of decline in specific muscle groups of patients with ALS and assesses whether there is a relationship between left and right muscles in the same patient, regardless of overall progression.MethodsA large cohort of patients was used to assess decline in muscle strength in right and left limbs over time using 2 different methods: The Tufts Quantitative Neuromuscular Exam and Accurate Test of Limb Isometric Strength protocol. Then advanced linear regression statistical methods were applied to assess progression rates in each limb.ResultsThis report shows that linearized progression models can predict general slopes of decline with good accuracy. Critically, the data demonstrate that while overall decline is variable, there is a high degree of correlation between left and right muscle decline in ALS. This implies that irrespective of which muscle starts declining soonest or latest, their rates of decline following onset are more consistent.ConclusionsFirst, this study demonstrates a high degree of power when using unilateral treatment approaches to detect a slowing in disease progression in smaller groups of patients, thus allowing for paired statistical tests. These findings will be useful in transplantation trials that use muscle decline to track disease progression in ALS. Second, these findings discuss methods, such as tactical selection of muscle groups, which can improve the power efficiency of all ALS clinical trials.
Published: 2017

27. Huntington's Disease iPSC-Derived Brain Microvascular Endothelial Cells Reveal WNT-Mediated Angiogenic and Blood-Brain Barrier Deficits.

Author: Lim, Ryan G, Lim, Ryan G, Quan, Chris, Reyes-Ortiz, Andrea M, Lutz, Sarah E, Kedaigle, Amanda J, Gipson, Theresa A, Wu, Jie, Vatine, Gad D, Stocksdale, Jennifer, Casale, Malcolm S, Svendsen, Clive N, Fraenkel, Ernest, Housman, David E, Agalliu, Dritan, Thompson, Leslie M, Lim, Ryan G, Lim, Ryan G, Quan, Chris, Reyes-Ortiz, Andrea M, Lutz, Sarah E, Kedaigle, Amanda J, Gipson, Theresa A, Wu, Jie, Vatine, Gad D, Stocksdale, Jennifer, Casale, Malcolm S, Svendsen, Clive N, Fraenkel, Ernest, Housman, David E, Agalliu, Dritan, and Thompson, Leslie M
Abstract: Brain microvascular endothelial cells (BMECs) are an essential component of the blood-brain barrier (BBB) that shields the brain against toxins and immune cells. While BBB dysfunction exists in neurological disorders, including Huntington's disease (HD), it is not known if BMECs themselves are functionally compromised to promote BBB dysfunction. Further, the underlying mechanisms of BBB dysfunction remain elusive given limitations with mouse models and post-mortem tissue to identify primary deficits. We undertook a transcriptome and functional analysis of human induced pluripotent stem cell (iPSC)-derived BMECs (iBMEC) from HD patients or unaffected controls. We demonstrate that HD iBMECs have intrinsic abnormalities in angiogenesis and barrier properties, as well as in signaling pathways governing these processes. Thus, our findings provide an iPSC-derived BBB model for a neurodegenerative disease and demonstrate autonomous neurovascular deficits that may underlie HD pathology with implications for therapeutics and drug delivery.
Published: 2017

28. Directed Differentiation of Human Induced Pluripotent Stem Cells into Fallopian Tube Epithelium.

Author: Yucer, Nur, Yucer, Nur, Holzapfel, Marie, Jenkins Vogel, Tilley, Lenaeus, Lindsay, Ornelas, Loren, Laury, Anna, Sareen, Dhruv, Barrett, Robert, Karlan, Beth Y, Svendsen, Clive N, Yucer, Nur, Yucer, Nur, Holzapfel, Marie, Jenkins Vogel, Tilley, Lenaeus, Lindsay, Ornelas, Loren, Laury, Anna, Sareen, Dhruv, Barrett, Robert, Karlan, Beth Y, and Svendsen, Clive N
Abstract: The fallopian tube epithelium (FTE) has been recognized as a site of origin of high-grade serous ovarian cancer (HGSC). However, the absence of relevant in vitro human models that can recapitulate tissue-specific architecture has hindered our understanding of FTE transformation and initiation of HGSC. Here, induced pluripotent stem cells (iPSCs) were used to establish a novel 3-dimensional (3D) human FTE organoid in vitro model containing the relevant cell types of the human fallopian tube as well as a luminal architecture that closely reflects the organization of fallopian tissues in vivo. Modulation of Wnt and BMP signaling directed iPSC differentiation into Müllerian cells and subsequent use of pro-Müllerian growth factors promoted FTE precursors. The expression and localization of Müllerian markers verified correct cellular differentiation. An innovative 3D growth platform, which enabled the FTE organoid to self-organize into a convoluted luminal structure, permitted matured differentiation to a FTE lineage. This powerful human-derived FTE organoid model can be used to study the earliest stages of HGSC development and to identify novel and specific biomarkers of early fallopian tube epithelial cell transformation.
Published: 2017

29. Concise Review: Stem Cells for Corneal Wound Healing.

Author: Saghizadeh, Mehrnoosh, Saghizadeh, Mehrnoosh, Kramerov, Andrei A, Svendsen, Clive N, Ljubimov, Alexander V, Saghizadeh, Mehrnoosh, Saghizadeh, Mehrnoosh, Kramerov, Andrei A, Svendsen, Clive N, and Ljubimov, Alexander V
Abstract: Corneal wound healing is a complex process that occurs in response to various injuries and commonly used refractive surgery. It is a significant clinical problem, which may lead to serious complications due to either incomplete (epithelial) or excessive (stromal) healing. Epithelial stem cells clearly play a role in this process, whereas the contribution of stromal and endothelial progenitors is less well studied. The available evidence on stem cell participation in corneal wound healing is reviewed, together with the data on the use of corneal and non-corneal stem cells to facilitate this process in diseased or postsurgical conditions. Important aspects of corneal stem cell generation from alternative cell sources, including pluripotent stem cells, for possible transplantation upon corneal injuries or in disease conditions are also presented. Stem Cells 2017;35:2105-2114.
Published: 2017

30. Modeling Psychomotor Retardation using iPSCs from MCT8-Deficient Patients Indicates a Prominent Role for the Blood-Brain Barrier.

Author: Vatine, Gad D, Vatine, Gad D, Al-Ahmad, Abraham, Barriga, Bianca K, Svendsen, Soshana, Salim, Ariel, Garcia, Leslie, Garcia, Veronica J, Ho, Ritchie, Yucer, Nur, Qian, Tongcheng, Lim, Ryan G, Wu, Jie, Thompson, Leslie M, Spivia, Weston R, Chen, Zhaohui, Van Eyk, Jennifer, Palecek, Sean P, Refetoff, Samuel, Shusta, Eric V, Svendsen, Clive N, Vatine, Gad D, Vatine, Gad D, Al-Ahmad, Abraham, Barriga, Bianca K, Svendsen, Soshana, Salim, Ariel, Garcia, Leslie, Garcia, Veronica J, Ho, Ritchie, Yucer, Nur, Qian, Tongcheng, Lim, Ryan G, Wu, Jie, Thompson, Leslie M, Spivia, Weston R, Chen, Zhaohui, Van Eyk, Jennifer, Palecek, Sean P, Refetoff, Samuel, Shusta, Eric V, and Svendsen, Clive N
Abstract: Inactivating mutations in the thyroid hormone (TH) transporter Monocarboxylate transporter 8 (MCT8) cause severe psychomotor retardation in children. Animal models do not reflect the biology of the human disease. Using patient-specific induced pluripotent stem cells (iPSCs), we generated MCT8-deficient neural cells that showed normal TH-dependent neuronal properties and maturation. However, the blood-brain barrier (BBB) controls TH entry into the brain, and reduced TH availability to neural cells could instead underlie the diseased phenotype. To test potential BBB involvement, we generated an iPSC-based BBB model of MCT8 deficiency, and we found that MCT8 was necessary for polarized influx of the active form of TH across the BBB. We also found that a candidate drug did not appreciably cross the mutant BBB. Our results therefore clarify the underlying physiological basis of this disorder, and they suggest that circumventing the diseased BBB to deliver active TH to the brain could be a viable therapeutic strategy.
Published: 2017

31. Cell freezing protocol suitable for ATAC-Seq on motor neurons derived from human induced pluripotent stem cells

Author: Massachusetts Institute of Technology. Computational and Systems Biology Program, Massachusetts Institute of Technology. Department of Biological Engineering, Milani, Pamela, Escalante, Renan A., Patel-Murray, Natasha Leanna, Xin, Xiaofeng, Adam, Miriam, Fraenkel, Ernest, Shelley, Brandon C., Mandefro, Berhan, Sareen, Dhruv, Svendsen, Clive N., Massachusetts Institute of Technology. Computational and Systems Biology Program, Massachusetts Institute of Technology. Department of Biological Engineering, Milani, Pamela, Escalante, Renan A., Patel-Murray, Natasha Leanna, Xin, Xiaofeng, Adam, Miriam, Fraenkel, Ernest, Shelley, Brandon C., Mandefro, Berhan, Sareen, Dhruv, and Svendsen, Clive N.
Abstract: In recent years, the assay for transposase-accessible chromatin using sequencing (ATAC-Seq) has become a fundamental tool of epigenomic research. However, it is difficult to perform this technique on frozen samples because freezing cells before extracting nuclei can impair nuclear integrity and alter chromatin structure, especially in fragile cells such as neurons. Our aim was to develop a protocol for freezing neuronal cells that is compatible with ATAC-Seq; we focused on a disease-relevant cell type, namely motor neurons differentiated from induced pluripotent stem cells (iMNs) from a patient affected by spinal muscular atrophy. We found that while flash-frozen iMNs are not suitable for ATAC-Seq, the assay is successful with slow-cooled cryopreserved cells. Using this method, we were able to isolate high quality, intact nuclei, and we verified that epigenetic results from fresh and cryopreserved iMNs quantitatively agree., National Institutes of Health (U.S.) (U54-NS-091046), National Institutes of Health (U.S.) (U01-CA-184898)
Published: 2017

32. Huntington’s Disease iPSC-Derived Brain Microvascular Endothelial Cells Reveal WNT-Mediated Angiogenic and Blood-Brain Barrier Deficits

Author: Massachusetts Institute of Technology. Department of Biology, Wasylenko, Theresa Anne, Housman, David E, Lim, Ryan G., Quan, Chris, Reyes-Ortiz, Andrea M., Lutz, Sarah E., Kedaigle, Amanda J., Wu, Jie, Vatine, Gad D., Stocksdale, Jennifer, Casale, Malcolm S., Svendsen, Clive N., Fraenkel, Ernest, Agalliu, Dritan, Thompson, Leslie M., Massachusetts Institute of Technology. Department of Biology, Wasylenko, Theresa Anne, Housman, David E, Lim, Ryan G., Quan, Chris, Reyes-Ortiz, Andrea M., Lutz, Sarah E., Kedaigle, Amanda J., Wu, Jie, Vatine, Gad D., Stocksdale, Jennifer, Casale, Malcolm S., Svendsen, Clive N., Fraenkel, Ernest, Agalliu, Dritan, and Thompson, Leslie M.
Abstract: Brain microvascular endothelial cells (BMECs) are an essential component of the blood-brain barrier (BBB) that shields the brain against toxins and immune cells. While BBB dysfunction exists in neurological disorders, including Huntington's disease (HD), it is not known if BMECs themselves are functionally compromised to promote BBB dysfunction. Further, the underlying mechanisms of BBB dysfunction remain elusive given limitations with mouse models and post-mortem tissue to identify primary deficits. We undertook a transcriptome and functional analysis of human induced pluripotent stem cell (iPSC)-derived BMECs (iBMEC) from HD patients or unaffected controls. We demonstrate that HD iBMECs have intrinsic abnormalities in angiogenesis and barrier properties, as well as in signaling pathways governing these processes. Thus, our findings provide an iPSC-derived BBB model for a neurodegenerative disease and demonstrate autonomous neurovascular deficits that may underlie HD pathology with implications for therapeutics and drug delivery., American Heart Association (12PRE10410000), American Heart Association (CIRMTG2-01152), National Institutes of Health (U.S.) (NIHNS089076)
Published: 2017

33. Cell freezing protocol suitable for ATAC-Seq on motor neurons derived from human induced pluripotent stem cells

Author: Massachusetts Institute of Technology. Computational and Systems Biology Program, Massachusetts Institute of Technology. Department of Biological Engineering, Milani, Pamela, Escalante, Renan A., Patel-Murray, Natasha Leanna, Xin, Xiaofeng, Adam, Miriam, Fraenkel, Ernest, Shelley, Brandon C., Mandefro, Berhan, Sareen, Dhruv, Svendsen, Clive N., Massachusetts Institute of Technology. Computational and Systems Biology Program, Massachusetts Institute of Technology. Department of Biological Engineering, Milani, Pamela, Escalante, Renan A., Patel-Murray, Natasha Leanna, Xin, Xiaofeng, Adam, Miriam, Fraenkel, Ernest, Shelley, Brandon C., Mandefro, Berhan, Sareen, Dhruv, and Svendsen, Clive N.
Abstract: In recent years, the assay for transposase-accessible chromatin using sequencing (ATAC-Seq) has become a fundamental tool of epigenomic research. However, it is difficult to perform this technique on frozen samples because freezing cells before extracting nuclei can impair nuclear integrity and alter chromatin structure, especially in fragile cells such as neurons. Our aim was to develop a protocol for freezing neuronal cells that is compatible with ATAC-Seq; we focused on a disease-relevant cell type, namely motor neurons differentiated from induced pluripotent stem cells (iMNs) from a patient affected by spinal muscular atrophy. We found that while flash-frozen iMNs are not suitable for ATAC-Seq, the assay is successful with slow-cooled cryopreserved cells. Using this method, we were able to isolate high quality, intact nuclei, and we verified that epigenetic results from fresh and cryopreserved iMNs quantitatively agree., National Institutes of Health (U.S.) (Grants U54-NS-091046 and U01-CA-184898)
Published: 2017

34. Neonatal immune-tolerance in mice does not prevent xenograft rejection.

Author: Mattis, Virginia B, Mattis, Virginia B, Wakeman, Dustin R, Tom, Colton, Dodiya, Hemraj B, Yeung, Sylvia Y, Tran, Andrew H, Bernau, Ksenija, Ornelas, Loren, Sahabian, Anais, Reidling, Jack, Sareen, Dhruv, Thompson, Leslie M, Kordower, Jeffrey H, Svendsen, Clive N, Mattis, Virginia B, Mattis, Virginia B, Wakeman, Dustin R, Tom, Colton, Dodiya, Hemraj B, Yeung, Sylvia Y, Tran, Andrew H, Bernau, Ksenija, Ornelas, Loren, Sahabian, Anais, Reidling, Jack, Sareen, Dhruv, Thompson, Leslie M, Kordower, Jeffrey H, and Svendsen, Clive N
Abstract: Assessing the efficacy of human stem cell transplantation in rodent models is complicated by the significant immune rejection that occurs. Two recent reports have shown conflicting results using neonatal tolerance to xenografts in rats. Here we extend this approach to mice and assess whether neonatal tolerance can prevent the rapid rejection of xenografts. In three strains of neonatal immune-intact mice, using two different brain transplant regimes and three independent stem cell types, we conclusively show that there is rapid rejection of the implanted cells. We also address specific challenges associated with the generation of humanized mouse models of disease.
Published: 2014

35. Rapid genetic targeting of pial surface neural progenitors and immature neurons by neonatal electroporation

Author: Breunig, Joshua J, Breunig, Joshua J, Gate, David, Levy, Rachelle, Rodriguez, Javier, Kim, Gi, Danielpour, Moise, Svendsen, Clive N, Town, Terrence, Breunig, Joshua J, Breunig, Joshua J, Gate, David, Levy, Rachelle, Rodriguez, Javier, Kim, Gi, Danielpour, Moise, Svendsen, Clive N, and Town, Terrence
Abstract: BackgroundRecent findings have indicated the presence of a progenitor domain at the marginal zone/layer 1 of the cerebral cortex, and it has been suggested that these progenitors have neurogenic and gliogenic potential. However, their contribution to the histogenesis of the cortex remains poorly understood due to difficulties associated with genetically manipulating these unique cells in a population-specific manner.ResultsWe have adapted the electroporation technique to target pial surface cells for rapid genetic manipulation at postnatal day 2. In vivo data show that most of these cells proliferate and progressively differentiate into both neuronal and glial subtypes. Furthermore, these cells localize to the superficial layers of the optic tectum and cerebral cortex prior to migration away from the surface.ConclusionsWe provide a foundation upon which future studies can begin to elucidate the molecular controls governing neural progenitor fate, migration, differentiation, and contribution to cortical and tectal histogenesis. Furthermore, specific genetic targeting of such neural progenitor populations will likely be of future clinical interest.
Published: 2012

36. Rapid genetic targeting of pial surface neural progenitors and immature neurons by neonatal electroporation

Author: Breunig, Joshua J, Breunig, Joshua J, Gate, David, Levy, Rachelle, Rodriguez, Javier, Kim, Gi, Danielpour, Moise, Svendsen, Clive N, Town, Terrence, Breunig, Joshua J, Breunig, Joshua J, Gate, David, Levy, Rachelle, Rodriguez, Javier, Kim, Gi, Danielpour, Moise, Svendsen, Clive N, and Town, Terrence
Abstract: BackgroundRecent findings have indicated the presence of a progenitor domain at the marginal zone/layer 1 of the cerebral cortex, and it has been suggested that these progenitors have neurogenic and gliogenic potential. However, their contribution to the histogenesis of the cortex remains poorly understood due to difficulties associated with genetically manipulating these unique cells in a population-specific manner.ResultsWe have adapted the electroporation technique to target pial surface cells for rapid genetic manipulation at postnatal day 2. In vivo data show that most of these cells proliferate and progressively differentiate into both neuronal and glial subtypes. Furthermore, these cells localize to the superficial layers of the optic tectum and cerebral cortex prior to migration away from the surface.ConclusionsWe provide a foundation upon which future studies can begin to elucidate the molecular controls governing neural progenitor fate, migration, differentiation, and contribution to cortical and tectal histogenesis. Furthermore, specific genetic targeting of such neural progenitor populations will likely be of future clinical interest.
Published: 2012

37. A novel serum-free method for culturing human prenatal retinal pigment epithelial cells

Author: Hospital Miguel Servet (Zaragoza). Servicio de Oftalmología, Gamm, David M., Melvan, J. Nicholas, Shearer, Rebecca L., Pinilla Lozano, Isabel, Sabat, Grzegorz, Svendsen, Clive N., Wright, Lynda S., Hospital Miguel Servet (Zaragoza). Servicio de Oftalmología, Gamm, David M., Melvan, J. Nicholas, Shearer, Rebecca L., Pinilla Lozano, Isabel, Sabat, Grzegorz, Svendsen, Clive N., and Wright, Lynda S.
Abstract: PURPOSE: Established techniques for culturing primary human retinal pigment epithelial (RPE) cells have facilitated the laboratory investigation of this multipurpose retinal cell layer. However, most culture methods involve the use of animal serum to establish and maintain RPE monolayers, which can complicate efforts to define and study factors involved in the maturation and function of these cells. Therefore, this study was conducted to develop a simple, serum-free system to propagate and sustain human RPE in vitro. METHODS: RPE was dissected from human prenatal donor eyes and cultured in serum-free defined medium containing the commercially formulated supplement B27 or N2. Cultures were grown initially as adherent tissue sections or suspended spherical aggregates and later expanded and maintained as monolayers. PCR, Western blot analysis, and immunocytochemistry were used to monitor gene and protein expression in established cultures, followed by examination of secretory products in RPE conditioned medium by ELISA and mass spectrometric analysis. RESULTS: In medium supplemented with B27, but not N2, RPE could be expanded up to 40,000-fold over six passages and maintained in culture for more than 1 year. In long-term cultures, typical cellular morphology and pigmentation were observed, along with expression of characteristic RPE markers. RPE monolayers also retained proper apical-basal orientation and secreted multiple factors implicated in the maintenance of photoreceptor health and the pathogenesis of age-related macular degeneration. CONCLUSIONS: Monolayer cultures of human prenatal RPE can be grown and maintained long term in the total absence of serum and still retain the phenotype, gene and protein expression profile, and secretory capacity exhibited by mature RPE cells.
Published: 2008

38. A novel serum-free method for culturing human prenatal retinal pigment epithelial cells

Author: Hospital Miguel Servet (Zaragoza). Servicio de Oftalmología, Gamm, David M., Melvan, J. Nicholas, Shearer, Rebecca L., Pinilla Lozano, Isabel, Sabat, Grzegorz, Svendsen, Clive N., Wright, Lynda S., Hospital Miguel Servet (Zaragoza). Servicio de Oftalmología, Gamm, David M., Melvan, J. Nicholas, Shearer, Rebecca L., Pinilla Lozano, Isabel, Sabat, Grzegorz, Svendsen, Clive N., and Wright, Lynda S.
Abstract: PURPOSE: Established techniques for culturing primary human retinal pigment epithelial (RPE) cells have facilitated the laboratory investigation of this multipurpose retinal cell layer. However, most culture methods involve the use of animal serum to establish and maintain RPE monolayers, which can complicate efforts to define and study factors involved in the maturation and function of these cells. Therefore, this study was conducted to develop a simple, serum-free system to propagate and sustain human RPE in vitro. METHODS: RPE was dissected from human prenatal donor eyes and cultured in serum-free defined medium containing the commercially formulated supplement B27 or N2. Cultures were grown initially as adherent tissue sections or suspended spherical aggregates and later expanded and maintained as monolayers. PCR, Western blot analysis, and immunocytochemistry were used to monitor gene and protein expression in established cultures, followed by examination of secretory products in RPE conditioned medium by ELISA and mass spectrometric analysis. RESULTS: In medium supplemented with B27, but not N2, RPE could be expanded up to 40,000-fold over six passages and maintained in culture for more than 1 year. In long-term cultures, typical cellular morphology and pigmentation were observed, along with expression of characteristic RPE markers. RPE monolayers also retained proper apical-basal orientation and secreted multiple factors implicated in the maintenance of photoreceptor health and the pathogenesis of age-related macular degeneration. CONCLUSIONS: Monolayer cultures of human prenatal RPE can be grown and maintained long term in the total absence of serum and still retain the phenotype, gene and protein expression profile, and secretory capacity exhibited by mature RPE cells.
Published: 2008

39. Regulated GDNF Delivery in Vivo Using Neural Stem Cells

Author: WISCONSIN UNIV-MADISON, Svendsen, Clive N., WISCONSIN UNIV-MADISON, and Svendsen, Clive N.
Abstract: The major aim of this proposal was to establish lines of neural stem cells secreting GDNF under a regulatable promoter system which may be used for future transplant therapies for PD. The tasks of the first year have been met. We have changed from using rodent and monkey stem cells to using human stem cells (hNSC) due to better growth and infection profiles for human cells. We have shown that hNSC can be infected with lenti-GDNF. GDNF released from the cells is functional on dopamine neurons and can be switched on and off by doxycycline. We have enhanced infection rates such that over 85% of cells express GDNF. We have selected high expressing lines and shown that they can be expanded in culture for over 20 weeks without losing the ability to produce GDNF in a regulated fashion. We have performed 6-OHDA lesions in rats to induce PD and shown loss of TH expression, survival of hNSC transplanted into these animals and expression of GDNF for up to 8 weeks (this is ahead of our predicted time frame) but are currently starting in vivo regulation studies. PET analysis has shown that the lesion can be detected with imaging and we are currently optimizing this protocol for use in the more detailed studies next year. Our pilot monkey work has been delayed due to problems growing the monkey stem cells. However, we have now scheduled the first surgery using hNSC for May 2004.
Published: 2004

40. Over-expression of alpha-synuclein in human neural progenitors leads to specific changes in fate and differentiation

Author: Schneider, Bernard L., Seehus, Corey R., Capowski, Elizabeth E., Aebischer, Patrick, Zhang, Su-Chun, Svendsen, Clive N., Schneider, Bernard L., Seehus, Corey R., Capowski, Elizabeth E., Aebischer, Patrick, Zhang, Su-Chun, and Svendsen, Clive N.
Abstract: Missense mutations and extra copies of the α-Synuclein gene result in Parkinson disease (PD). Human stem and progenitor cells can be expanded from embryonic tissues and provide a source of non-transformed neural cells to explore the effects of these pathogenic mutations specifically in human nervous tissue. We over-expressed the wild type, A53T and A30P forms of α-synuclein in expanded populations of progenitors derived from the human fetal cortex. The protein localized in the nucleus and around microvesicles. Only the A53T form was acutely toxic, suggesting a unique vulnerability of these progenitors to this mutation. Interestingly, constitutive over-expression of wild-type α-synuclein progressively impaired the innate ability of progenitors to switch toward gliogenesis at later passages. To explore the effect of α-synuclein on neuronal subtypes selectively affected in PD, such as dopaminergic neurons, α-synuclein and its mutations were also over-expressed in terminally differentiating neuroectodermal cultures derived from human embryonic stem cells (hESC). Alpha-synuclein induced acute cytotoxicity and reduced the number of neurons expressing either tyrosine hydroxylase or gamma-aminobutyric acid over time. Consistent with the selective vulnerability of ventral midbrain dopaminergic neurons, α-synuclein cytotoxicity appeared most pronounced following FGF8/SHH specification and was decreased by inhibition of dopamine synthesis. Together, these data show that α-synuclein over-expressed in human neural embryonic cells results in patterns of degeneration that in some cases match features of Parkinson Disease. Thus, neural cells derived from hESC provide a useful model system to understand the development of α-synuclein-related pathologies and allow therapeutic drug screening

Catalog

Books, media, physical & digital resources

See catalog results

Searchworks

Select search scope, currently: Articles Catalog books, media & more in Jio Institute collections Articles journal articles & other e-resources

Search

Search Constraints

Refine your results

Search Limiters

Publication Year Range

Publication Type

Database

Publisher

40 results on '"Svendsen, Clive N."'

Search Results

Catalog

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources