Search

Your search keyword '"Rothstein, Jeffrey D"' showing total 949 results
Start Over Author "Rothstein, Jeffrey D"
949 results on '"Rothstein, Jeffrey D"'

4. Large-scale differentiation of iPSC-derived motor neurons from ALS and control subjects

Author

Workman, Michael J, Lim, Ryan G, Wu, Jie, Frank, Aaron, Ornelas, Loren, Panther, Lindsay, Galvez, Erick, Perez, Daniel, Meepe, Imara, Lei, Susan, Valencia, Viviana, Gomez, Emilda, Liu, Chunyan, Moran, Ruby, Pinedo, Louis, Tsitkov, Stanislav, Ho, Ritchie, Kaye, Julia A, Consortium, the Answer ALS, Thompson, Terri, Rothstein, Jeffrey D, Finkbeiner, Steven, Fraenkel, Ernest, Sareen, Dhruv, Thompson, Leslie M, and Svendsen, Clive N

Subjects
Biomedical and Clinical Sciences, Neurosciences, Brain Disorders, Clinical Research, Stem Cell Research - Induced Pluripotent Stem Cell - Human, Rare Diseases, Stem Cell Research - Induced Pluripotent Stem Cell, Regenerative Medicine, Genetics, Neurodegenerative, Stem Cell Research, ALS, Orphan Drug, Neurological, Humans, Amyotrophic Lateral Sclerosis, Induced Pluripotent Stem Cells, Motor Neurons, Cell Differentiation, Answer ALS Consortium, iPSC, motor neurons, sex differences, Psychology, Cognitive Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

Using induced pluripotent stem cells (iPSCs) to understand the mechanisms of neurological disease holds great promise; however, there is a lack of well-curated lines from a large array of participants. Answer ALS has generated over 1,000 iPSC lines from control and amyotrophic lateral sclerosis (ALS) patients along with clinical and whole-genome sequencing data. The current report summarizes cell marker and gene expression in motor neuron cultures derived from 92 healthy control and 341 ALS participants using a 32-day differentiation protocol. This is the largest set of iPSCs to be differentiated into motor neurons, and characterization suggests that cell composition and sex are significant sources of variability that need to be carefully controlled for in future studies. These data are reported as a resource for the scientific community that will utilize Answer ALS data for disease modeling using a wider array of omics being made available for these samples.

Published
2023

5. Effect of sodium phenylbutyrate/taurursodiol on tracheostomy/ventilation-free survival and hospitalisation in amyotrophic lateral sclerosis: long-term results from the CENTAUR trial

Author

Paganoni, Sabrina, Hendrix, Suzanne, Dickson, Samuel P, Knowlton, Newman, Berry, James D, Elliott, Michael A, Maiser, Samuel, Karam, Chafic, Caress, James B, Owegi, Margaret Ayo, Quick, Adam, Wymer, James, Goutman, Stephen A, Heitzman, Daragh, Heiman-Patterson, Terry D, Jackson, Carlayne, Quinn, Colin, Rothstein, Jeffrey D, Kasarskis, Edward J, Katz, Jonathan, Jenkins, Liberty, Ladha, Shafeeq S, Miller, Timothy M, Scelsa, Stephen N, Vu, Tuan H, Fournier, Christina, Johnson, Kristin M, Swenson, Andrea, Goyal, Namita, Pattee, Gary L, Babu, Suma, Chase, Marianne, Dagostino, Derek, Hall, Meghan, Kittle, Gale, Eydinov, Mathew, Ostrow, Joseph, Pothier, Lindsay, Randall, Rebecca, Shefner, Jeremy M, Sherman, Alexander V, Tustison, Eric, Vigneswaran, Prasha, Yu, Hong, Cohen, Joshua, Klee, Justin, Tanzi, Rudolph, Gilbert, Walter, Yeramian, Patrick, and Cudkowicz, Merit

Subjects
Rare Diseases, ALS, Neurosciences, Clinical Research, Clinical Trials and Supportive Activities, Neurodegenerative, Brain Disorders, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, MOTOR NEURON DISEASE, NEUROMUSCULAR, RANDOMISED TRIALS, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery
Abstract

BackgroundCoformulated sodium phenylbutyrate/taurursodiol (PB/TURSO) was shown to prolong survival and slow functional decline in amyotrophic lateral sclerosis (ALS).ObjectiveDetermine whether PB/TURSO prolonged tracheostomy/ventilation-free survival and/or reduced first hospitalisation in participants with ALS in the CENTAUR trial.MethodsAdults with El Escorial Definite ALS ≤18 months from symptom onset were randomised to PB/ TURSO or placebo for 6 months. Those completing randomised treatment could enrol in an open-label extension (OLE) phase and receive PB/TURSO for ≤30 months. Times to the following individual or combined key events were compared in the originally randomised treatment groups over a period spanning trial start through July 2020 (longest postrandomisation follow-up, 35 months): death, tracheostomy, permanent assisted ventilation (PAV) and first hospitalisation.ResultsRisk of any key event was 47% lower in those originally randomised to PB/TURSO (n=87) versus placebo (n=48, 71% of whom received delayed-start PB/TURSO in the OLE phase) (HR=0.53; 95% CI 0.35 to 0.81; p=0.003). Risks of death or tracheostomy/PAV (HR=0.51; 95% CI 0.32 to 0.84; p=0.007) and first hospitalisation (HR=0.56; 95% CI 0.34 to 0.95; p=0.03) were also decreased in those originally randomised to PB/TURSO.ConclusionsEarly PB/TURSO prolonged tracheostomy/PAV-free survival and delayed first hospitalisation in ALS.Trial registration numberNCT03127514; NCT03488524.

Published
2022

6. Safety, tolerability, and pharmacokinetics of antisense oligonucleotide BIIB078 in adults with C9orf72-associated amyotrophic lateral sclerosis: a phase 1, randomised, double blinded, placebo-controlled, multiple ascending dose study

Author

van den Berg, Leonard H, Rothstein, Jeffrey D, Shaw, Pamela J, Babu, Suma, Benatar, Michael, Bucelli, Robert C, Genge, Angela, Glass, Jonathan D, Hardiman, Orla, Libri, Vincenzo, Mobach, Theodore, Oskarsson, Björn, Pattee, Gary L, Ravits, John, Shaw, Christopher E, Weber, Markus, Zinman, Lorne, Jafar-nejad, Paymaan, Rigo, Frank, Lin, Luan, Ferguson, Toby A, Gotter, Anthony L, Graham, Danielle, Monine, Michael, Inra, Jennifer, Sinks, Susie, Eraly, Satish, Garafalo, Steve, and Fradette, Stephanie

Published
2024
Full Text
View/download PDF

7. Reactive astrocyte nomenclature, definitions, and future directions

Author

Escartin, Carole, Galea, Elena, Lakatos, András, O’Callaghan, James P, Petzold, Gabor C, Serrano-Pozo, Alberto, Steinhäuser, Christian, Volterra, Andrea, Carmignoto, Giorgio, Agarwal, Amit, Allen, Nicola J, Araque, Alfonso, Barbeito, Luis, Barzilai, Ari, Bergles, Dwight E, Bonvento, Gilles, Butt, Arthur M, Chen, Wei-Ting, Cohen-Salmon, Martine, Cunningham, Colm, Deneen, Benjamin, De Strooper, Bart, Díaz-Castro, Blanca, Farina, Cinthia, Freeman, Marc, Gallo, Vittorio, Goldman, James E, Goldman, Steven A, Götz, Magdalena, Gutiérrez, Antonia, Haydon, Philip G, Heiland, Dieter H, Hol, Elly M, Holt, Matthew G, Iino, Masamitsu, Kastanenka, Ksenia V, Kettenmann, Helmut, Khakh, Baljit S, Koizumi, Schuichi, Lee, C Justin, Liddelow, Shane A, MacVicar, Brian A, Magistretti, Pierre, Messing, Albee, Mishra, Anusha, Molofsky, Anna V, Murai, Keith K, Norris, Christopher M, Okada, Seiji, Oliet, Stéphane HR, Oliveira, João F, Panatier, Aude, Parpura, Vladimir, Pekna, Marcela, Pekny, Milos, Pellerin, Luc, Perea, Gertrudis, Pérez-Nievas, Beatriz G, Pfrieger, Frank W, Poskanzer, Kira E, Quintana, Francisco J, Ransohoff, Richard M, Riquelme-Perez, Miriam, Robel, Stefanie, Rose, Christine R, Rothstein, Jeffrey D, Rouach, Nathalie, Rowitch, David H, Semyanov, Alexey, Sirko, Swetlana, Sontheimer, Harald, Swanson, Raymond A, Vitorica, Javier, Wanner, Ina-Beate, Wood, Levi B, Wu, Jiaqian, Zheng, Binhai, Zimmer, Eduardo R, Zorec, Robert, Sofroniew, Michael V, and Verkhratsky, Alexei

Subjects
Neurosciences, Brain Disorders, Neurological, Aging, Animals, Astrocytes, Brain, Brain Diseases, Brain Injuries, Humans, Spinal Cord, Spinal Cord Injuries, Psychology, Cognitive Sciences, Neurology & Neurosurgery
Abstract

Reactive astrocytes are astrocytes undergoing morphological, molecular, and functional remodeling in response to injury, disease, or infection of the CNS. Although this remodeling was first described over a century ago, uncertainties and controversies remain regarding the contribution of reactive astrocytes to CNS diseases, repair, and aging. It is also unclear whether fixed categories of reactive astrocytes exist and, if so, how to identify them. We point out the shortcomings of binary divisions of reactive astrocytes into good-vs-bad, neurotoxic-vs-neuroprotective or A1-vs-A2. We advocate, instead, that research on reactive astrocytes include assessment of multiple molecular and functional parameters-preferably in vivo-plus multivariate statistics and determination of impact on pathological hallmarks in relevant models. These guidelines may spur the discovery of astrocyte-based biomarkers as well as astrocyte-targeting therapies that abrogate detrimental actions of reactive astrocytes, potentiate their neuro- and glioprotective actions, and restore or augment their homeostatic, modulatory, and defensive functions.

Published
2021

8. Long‐term survival of participants in the CENTAUR trial of sodium phenylbutyrate‐taurursodiol in amyotrophic lateral sclerosis

Author

Paganoni, Sabrina, Hendrix, Suzanne, Dickson, Samuel P, Knowlton, Newman, Macklin, Eric A, Berry, James D, Elliott, Michael A, Maiser, Samuel, Karam, Chafic, Caress, James B, Owegi, Margaret Ayo, Quick, Adam, Wymer, James, Goutman, Stephen A, Heitzman, Daragh, Heiman‐Patterson, Terry D, Jackson, Carlayne E, Quinn, Colin, Rothstein, Jeffrey D, Kasarskis, Edward J, Katz, Jonathan, Jenkins, Liberty, Ladha, Shafeeq, Miller, Timothy M, Scelsa, Stephen N, Vu, Tuan H, Fournier, Christina N, Glass, Jonathan D, Johnson, Kristin M, Swenson, Andrea, Goyal, Namita A, Pattee, Gary L, Andres, Patricia L, Babu, Suma, Chase, Marianne, Dagostino, Derek, Hall, Meghan, Kittle, Gale, Eydinov, Matthew, McGovern, Michelle, Ostrow, Joseph, Pothier, Lindsay, Randall, Rebecca, Shefner, Jeremy M, Sherman, Alexander V, St Pierre, Maria E, Tustison, Eric, Vigneswaran, Prasha, Walker, Jason, Yu, Hong, Chan, James, Wittes, Janet, Yu, Zi‐Fan, Cohen, Joshua, Klee, Justin, Leslie, Kent, Tanzi, Rudolph E, Gilbert, Walter, Yeramian, Patrick D, Schoenfeld, David, and Cudkowicz, Merit E

Subjects
Brain Disorders, Rare Diseases, Neurodegenerative, Clinical Trials and Supportive Activities, Clinical Research, ALS, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Adolescent, Adult, Aged, Aged, 80 and over, Amyotrophic Lateral Sclerosis, Double-Blind Method, Female, Humans, Male, Middle Aged, Neuroprotective Agents, Phenylbutyrates, Taurochenodeoxycholic Acid, Time, Young Adult, amyotrophic lateral sclerosis, CENTAUR, motor neuron disease, sodium phenylbutyrate&#8208, taurursodiol, survival analysis, sodium phenylbutyrate-taurursodiol, Medical and Health Sciences, Neurology & Neurosurgery
Abstract

An orally administered, fixed-dose coformulation of sodium phenylbutyrate-taurursodiol (PB-TURSO) significantly slowed functional decline in a randomized, placebo-controlled, phase 2 trial in ALS (CENTAUR). Herein we report results of a long-term survival analysis of participants in CENTAUR. In CENTAUR, adults with ALS were randomized 2:1 to PB-TURSO or placebo. Participants completing the 6-month (24-week) randomized phase were eligible to receive PB-TURSO in the open-label extension. An all-cause mortality analysis (35-month maximum follow-up post-randomization) incorporated all randomized participants. Participants and site investigators were blinded to treatment assignments through the duration of follow-up of this analysis. Vital status was obtained for 135 of 137 participants originally randomized in CENTAUR. Median overall survival was 25.0 months among participants originally randomized to PB-TURSO and 18.5 months among those originally randomized to placebo (hazard ratio, 0.56; 95% confidence interval, 0.34-0.92; P = .023). Initiation of PB-TURSO treatment at baseline resulted in a 6.5-month longer median survival as compared with placebo. Combined with results from CENTAUR, these results suggest that PB-TURSO has both functional and survival benefits in ALS.

Published
2021

9. Genome-wide structural variant analysis identifies risk loci for non-Alzheimer’s dementias

Author

Soltis, Anthony R., Viollet, Coralie, Sukumar, Gauthaman, Alba, Camille, Lott, Nathaniel, McGrath Martinez, Elisa, Tuck, Meila, Singh, Jatinder, Bacikova, Dagmar, Zhang, Xijun, Hupalo, Daniel N., Adeleye, Adelani, Wilkerson, Matthew D., Pollard, Harvey B., Dalgard, Clifton L., Black, Sandra E., Gan-Or, Ziv, Keith, Julia, Masellis, Mario, Rogaeva, Ekaterina, Brice, Alexis, Lesage, Suzanne, Xiromerisiou, Georgia, Calvo, Andrea, Canosa, Antonio, Chio, Adriano, Logroscino, Giancarlo, Mora, Gabriele, Krüger, Reijko, May, Patrick, Alcolea, Daniel, Clarimon, Jordi, Fortea, Juan, Gonzalez-Aramburu, Isabel, Infante, Jon, Lage, Carmen, Lleó, Alberto, Pastor, Pau, Sanchez-Juan, Pascual, Brett, Francesca, Aarsland, Dag, Al-Sarraj, Safa, Attems, Johannes, Gentleman, Steve, Hardy, John A., Hodges, Angela K., Love, Seth, McKeith, Ian G., Morris, Christopher M., Morris, Huw R., Palmer, Laura, Pickering-Brown, Stuart, Ryten, Mina, Thomas, Alan J., Troakes, Claire, Albert, Marilyn S., Barrett, Matthew J., Beach, Thomas G., Bekris, Lynn M., Bennett, David A., Boeve, Bradley F., Dawson, Ted M., Dickson, Dennis W., Faber, Kelley, Ferman, Tanis, Ferrucci, Luigi, Flanagan, Margaret E., Foroud, Tatiana M., Ghetti, Bernardino, Gibbs, J. Raphael, Goate, Alison, Goldstein, David S., Graff-Radford, Neill R., Kaufmann, Horacio, Kukull, Walter A., Leverenz, James B., Lopez, Grisel, Mao, Qinwen, Masliah, Eliezer, Monuki, Edwin, Newell, Kathy L., Palma, Jose-Alberto, Perkins, Matthew, Pletnikova, Olga, Renton, Alan E., Resnick, Susan M., Rosenthal, Liana S., Ross, Owen A., Scherzer, Clemens R., Serrano, Geidy E., Shakkottai, Vikram G., Sidransky, Ellen, Tanaka, Toshiko, Tayebi, Nahid, Topol, Eric, Torkamani, Ali, Troncoso, Juan C., Woltjer, Randy, Wszolek, Zbigniew K., Scholz, Sonja W., Baloh, Robert H., Bowser, Robert, Broach, James, Camu, William, Chiò, Adriano, Cooper-Knock, John, Drepper, Carsten, Drory, Vivian E., Dunckley, Travis L., Feldman, Eva, Fratta, Pietro, Gerhard, Glenn, Gibson, Summer B., Glass, Jonathan D., Harms, Matthew B., Heiman-Patterson, Terry D., Jansson, Lilja, Kirby, Janine, Kwan, Justin, Laaksovirta, Hannu, Landers, John E., Landi, Francesco, Le Ber, Isabelle, Lumbroso, Serge, MacGowan, Daniel J.L., Maragakis, Nicholas J., Mouzat, Kevin, Myllykangas, Liisa, Orrell, Richard W., Ostrow, Lyle W., Pamphlett, Roger, Pioro, Erik, Pulst, Stefan M., Ravits, John M., Robberecht, Wim, Rothstein, Jeffrey D., Sendtner, Michael, Shaw, Pamela J., Sidle, Katie C., Simmons, Zachary, Stein, Thor, Stone, David J., Tienari, Pentti J., Traynor, Bryan J., Valori, Miko, Van Damme, Philip, Van Deerlin, Vivianna M., Van Den Bosch, Ludo, Zinman, Lorne, Kaivola, Karri, Chia, Ruth, Ding, Jinhui, Rasheed, Memoona, Fujita, Masashi, Menon, Vilas, Walton, Ronald L., Collins, Ryan L., Billingsley, Kimberley, Brand, Harrison, Talkowski, Michael, Zhao, Xuefang, Dewan, Ramita, Stark, Ali, Ray, Anindita, Solaiman, Sultana, Alvarez Jerez, Pilar, Malik, Laksh, Tienari, Pentti, Mazzini, Letizia, D'Alfonso, Sandra, Moglia, Cristina, and De Jager, Philip L.

Published
2023
Full Text
View/download PDF

10. Trial of Sodium Phenylbutyrate–Taurursodiol for Amyotrophic Lateral Sclerosis

Author

Paganoni, Sabrina, Macklin, Eric A, Hendrix, Suzanne, Berry, James D, Elliott, Michael A, Maiser, Samuel, Karam, Chafic, Caress, James B, Owegi, Margaret A, Quick, Adam, Wymer, James, Goutman, Stephen A, Heitzman, Daragh, Heiman-Patterson, Terry, Jackson, Carlayne E, Quinn, Colin, Rothstein, Jeffrey D, Kasarskis, Edward J, Katz, Jonathan, Jenkins, Liberty, Ladha, Shafeeq, Miller, Timothy M, Scelsa, Stephen N, Vu, Tuan H, Fournier, Christina N, Glass, Jonathan D, Johnson, Kristin M, Swenson, Andrea, Goyal, Namita A, Pattee, Gary L, Andres, Patricia L, Babu, Suma, Chase, Marianne, Dagostino, Derek, Dickson, Samuel P, Ellison, Noel, Hall, Meghan, Hendrix, Kent, Kittle, Gale, McGovern, Michelle, Ostrow, Joseph, Pothier, Lindsay, Randall, Rebecca, Shefner, Jeremy M, Sherman, Alexander V, Tustison, Eric, Vigneswaran, Prasha, Walker, Jason, Yu, Hong, Chan, James, Wittes, Janet, Cohen, Joshua, Klee, Justin, Leslie, Kent, Tanzi, Rudolph E, Gilbert, Walter, Yeramian, Patrick D, Schoenfeld, David, and Cudkowicz, Merit E

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Clinical Trials and Supportive Activities, Neurodegenerative, Rare Diseases, Clinical Research, ALS, Brain Disorders, Neurosciences, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Aged, Amyotrophic Lateral Sclerosis, Disease Progression, Double-Blind Method, Drug Combinations, Female, Humans, Intention to Treat Analysis, Male, Middle Aged, Phenylbutyrates, Severity of Illness Index, Taurochenodeoxycholic Acid, Treatment Outcome, Medical and Health Sciences, General & Internal Medicine, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundSodium phenylbutyrate and taurursodiol have been found to reduce neuronal death in experimental models. The efficacy and safety of a combination of the two compounds in persons with amyotrophic lateral sclerosis (ALS) are not known.MethodsIn this multicenter, randomized, double-blind trial, we enrolled participants with definite ALS who had had an onset of symptoms within the previous 18 months. Participants were randomly assigned in a 2:1 ratio to receive sodium phenylbutyrate-taurursodiol (3 g of sodium phenylbutyrate and 1 g of taurursodiol, administered once a day for 3 weeks and then twice a day) or placebo. The primary outcome was the rate of decline in the total score on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) through 24 weeks. Secondary outcomes were the rates of decline in isometric muscle strength, plasma phosphorylated axonal neurofilament H subunit levels, and the slow vital capacity; the time to death, tracheostomy, or permanent ventilation; and the time to death, tracheostomy, permanent ventilation, or hospitalization.ResultsA total of 177 persons with ALS were screened for eligibility, and 137 were randomly assigned to receive sodium phenylbutyrate-taurursodiol (89 participants) or placebo (48 participants). In a modified intention-to-treat analysis, the mean rate of change in the ALSFRS-R score was -1.24 points per month with the active drug and -1.66 points per month with placebo (difference, 0.42 points per month; 95% confidence interval, 0.03 to 0.81; P = 0.03). Secondary outcomes did not differ significantly between the two groups. Adverse events with the active drug were mainly gastrointestinal.ConclusionsSodium phenylbutyrate-taurursodiol resulted in slower functional decline than placebo as measured by the ALSFRS-R score over a period of 24 weeks. Secondary outcomes were not significantly different between the two groups. Longer and larger trials are necessary to evaluate the efficacy and safety of sodium phenylbutyrate-taurursodiol in persons with ALS. (Funded by Amylyx Pharmaceuticals and others; CENTAUR ClinicalTrials.gov number, NCT03127514.).

Published
2020

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

Author

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

Subjects
Biomedical and Clinical Sciences, Neurosciences, Alzheimer's Disease Related Dementias (ADRD), Rare Diseases, Frontotemporal Dementia (FTD), ALS, Stem Cell Research - Induced Pluripotent Stem Cell - Human, Genetics, Neurodegenerative, Brain Disorders, Acquired Cognitive Impairment, Stem Cell Research, Stem Cell Research - Induced Pluripotent Stem Cell, Dementia, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurological, Active Transport, Cell Nucleus, Amyotrophic Lateral Sclerosis, C9orf72 Protein, Cells, Cultured, Frontotemporal Dementia, HEK293 Cells, Humans, Induced Pluripotent Stem Cells, Membrane Glycoproteins, Neural Stem Cells, Nuclear Pore, Nuclear Pore Complex Proteins, C9orf72, FTD, POM121, neurodegeneration, nuclear pore complex, Psychology, Cognitive Sciences, Neurology & Neurosurgery, Biological psychology
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

12. CRISPR-Cas9 Screens Identify the RNA Helicase DDX3X as a Repressor of C9ORF72 (GGGGCC)n Repeat-Associated Non-AUG Translation

Author

Cheng, Weiwei, Wang, Shaopeng, Zhang, Zhe, Morgens, David W, Hayes, Lindsey R, Lee, Soojin, Portz, Bede, Xie, Yongzhi, Nguyen, Baotram V, Haney, Michael S, Yan, Shirui, Dong, Daoyuan, Coyne, Alyssa N, Yang, Junhua, Xian, Fengfan, Cleveland, Don W, Qiu, Zhaozhu, Rothstein, Jeffrey D, Shorter, James, Gao, Fen-Biao, Bassik, Michael C, and Sun, Shuying

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Neurosciences, Psychology, Frontotemporal Dementia (FTD), Brain Disorders, Neurodegenerative, ALS, Acquired Cognitive Impairment, Dementia, Rare Diseases, Genetics, 2.1 Biological and endogenous factors, Aetiology, Neurological, Amyotrophic Lateral Sclerosis, Animals, C9orf72 Protein, CRISPR-Cas Systems, DEAD-box RNA Helicases, Drosophila, Frontotemporal Dementia, Humans, Protein Biosynthesis, Repetitive Sequences, Nucleic Acid, CRISPR-Cas9 screen, DDX3X, FTD, RAN translation, RNA, helicase, neurodegeneration, repeat expansion, Cognitive Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

Hexanucleotide GGGGCC repeat expansion in C9ORF72 is the most prevalent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). One pathogenic mechanism is the aberrant accumulation of dipeptide repeat (DPR) proteins produced by the unconventional translation of expanded RNA repeats. Here, we performed genome-wide CRISPR-Cas9 screens for modifiers of DPR protein production in human cells. We found that DDX3X, an RNA helicase, suppresses the repeat-associated non-AUG translation of GGGGCC repeats. DDX3X directly binds to (GGGGCC)n RNAs but not antisense (CCCCGG)n RNAs. Its helicase activity is essential for the translation repression. Reduction of DDX3X increases DPR levels in C9ORF72-ALS/FTD patient cells and enhances (GGGGCC)n-mediated toxicity in Drosophila. Elevating DDX3X expression is sufficient to decrease DPR levels, rescue nucleocytoplasmic transport abnormalities, and improve survival of patient iPSC-differentiated neurons. This work identifies genetic modifiers of DPR protein production and provides potential therapeutic targets for C9ORF72-ALS/FTD.

Published
2019

15. 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., 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., and Rothstein, Jeffrey D.

Published
2022
Full Text
View/download PDF

16. Apilimod dimesylate in C9orf72 amyotrophic lateral sclerosis: a randomized phase 2a clinical trial.

Author

Babu, Suma, Nicholson, Katharine A, Rothstein, Jeffrey D, Swenson, Andrea, Sampognaro, Paul J, Pant, Pravin, Macklin, Eric A, Spruill, Susan, Paganoni, Sabrina, Gendron, Tania F, Prudencio, Mercedes, Petrucelli, Leonard, Nix, Darrell, Landrette, Sean, Nkrumah, Esther, Fandrick, Keith, Edwards, Joan, and Young, Peter R

Subjects
AMYOTROPHIC lateral sclerosis, BLOOD proteins, BIOMARKERS, ORAL drug administration, CLINICAL trials
Abstract

Apilimod dimesylate is a first-in-class phosphoinositide kinase, FYVE-type zinc finger-containing (PIKfyve) inhibitor with a favourable clinical safety profile and has demonstrated activity in preclinical C9orf72 and TDP-43 amyotrophic lateral sclerosis (ALS) models. In this ALS clinical trial, the safety, tolerability, CNS penetrance and modulation of pharmacodynamic target engagement biomarkers were evaluated. This phase 2a, randomized, double-blind, placebo-controlled, biomarker-end-point clinical trial was conducted in four US centres (ClinicalTrials.gov NCT05163886). Participants with C9orf72 repeat expansions were randomly assigned (2:1) to receive twice-daily oral treatment with 125 mg apilimod dimesylate capsules or matching placebo for 12 weeks, followed by a 12-week open-label extension. Safety was measured as the occurrence of treatment-emergent or serious adverse events attributable to the study drug and tolerability at trial completion or treatment over 12 weeks. Changes from baseline in plasma and CSF and concentrations of apilimod dimesylate and its active metabolites and of pharmacodynamic biomarkers of PIKfyve inhibition [soluble glycoprotein nonmetastatic melanoma protein B (sGPNMB) upregulation] and disease-specific CNS target engagement [poly(GP)] were measured. Between 16 December 2021 and 7 July 2022, 15 eligible participants were enrolled. There were no drug-related serious adverse events reported in the trial. Fourteen (93%) participants completed the double-blind period with 99% dose compliance [ n = 9 (90%) apilimod dimesylate; n = 5 (100%) placebo]. At Week 12, apilimod dimesylate was measurable in CSF at 1.63 ng/ml [standard deviation (SD): 0.937]. At Week 12, apilimod dimesylate increased plasma sGPNMB by >2.5-fold (P < 0.001), indicating PIKfyve inhibition, and lowered CSF poly(GP) protein levels by 73% (P < 0.001), indicating CNS tissue-level proof of mechanism. Apilimod dimesylate met prespecified key safety and biomarker end-points in this phase 2a trial and demonstrated CNS penetrance and pharmacodynamic target engagement. Apilimod dimesylate was observed to result in the greatest reduction in CSF poly(GP) levels observed to date in C9orf72 clinical trials. [ABSTRACT FROM AUTHOR]

Published
2024
Full Text
View/download PDF

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

Author

Phatnani, Hemali, Kwan, Justin, Sareen, Dhruv, Broach, James R., Simmons, Zachary, Arcila-Londono, Ximena, Lee, Edward B., Van Deerlin, Vivianna M., Shneider, Neil A., Fraenkel, Ernest, Ostrow, Lyle W., Baas, Frank, Zaitlen, Noah, Berry, James D., Malaspina, Andrea, Fratta, Pietro, Cox, Gregory A., Thompson, Leslie M., Finkbeiner, Steve, Dardiotis, Efthimios, Miller, Timothy M., Chandran, Siddharthan, Pal, Suvankar, Hornstein, Eran, MacGowan, Daniel J., Heiman-Patterson, Terry, Hammell, Molly G., Patsopoulos, Nikolaos.A., Butovsky, Oleg, Dubnau, Joshua, Nath, Avindra, Bowser, Robert, Harms, Matt, Poss, Mary, Phillips-Cremins, Jennifer, Crary, John, Atassi, Nazem, Lange, Dale J., Adams, Darius J., Stefanis, Leonidas, Gotkine, Marc, Baloh, Robert H., Babu, Suma, Raj, Towfique, Paganoni, Sabrina, Shalem, Ophir, Smith, Colin, Zhang, Bin, Harris, Brent, Broce, Iris, Drory, Vivian, Ravits, John, McMillan, Corey, Menon, Vilas, Wu, Lani, Altschuler, Steven, 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, Van Eyk, Jennifer E., Lloyd, Thomas E., Finkbeiner, Steven, Rothstein, Jeffrey D., and Svendsen, Clive N.

Published
2021
Full Text
View/download PDF

19. Mutant Huntingtin Disrupts the Nuclear Pore Complex

Author

Grima, Jonathan C, Daigle, J Gavin, Arbez, Nicolas, Cunningham, Kathleen C, Zhang, Ke, Ochaba, Joseph, Geater, Charlene, Morozko, Eva, Stocksdale, Jennifer, Glatzer, Jenna C, Pham, Jacqueline T, Ahmed, Ishrat, Peng, Qi, Wadhwa, Harsh, Pletnikova, Olga, Troncoso, Juan C, Duan, Wenzhen, Snyder, Solomon H, Ranum, Laura PW, Thompson, Leslie M, Lloyd, Thomas E, Ross, Christopher A, and Rothstein, Jeffrey D

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Neurosciences, Psychology, Orphan Drug, Brain Disorders, Neurodegenerative, Huntington's Disease, Rare Diseases, 2.1 Biological and endogenous factors, Aetiology, Neurological, Active Transport, Cell Nucleus, Adult, Animals, Disease Models, Animal, Drosophila, Drosophila Proteins, Female, Humans, Huntingtin Protein, Huntington Disease, Induced Pluripotent Stem Cells, Male, Mice, Middle Aged, Mutation, Nuclear Pore, Nuclear Pore Complex Proteins, Young Adult, C9ORF72, Huntington’s disease, KPT-350, O-GlcNAc, RAN translation, Thiamet-G, induced pluripotent stem cell, neurodegeneration, nuclear pore complex, nucleocytoplasmic transport, Cognitive Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

Huntington's disease (HD) is caused by an expanded CAG repeat in the Huntingtin (HTT) gene. The mechanism(s) by which mutant HTT (mHTT) causes disease is unclear. Nucleocytoplasmic transport, the trafficking of macromolecules between the nucleus and cytoplasm, is tightly regulated by nuclear pore complexes (NPCs) made up of nucleoporins (NUPs). Previous studies offered clues that mHTT may disrupt nucleocytoplasmic transport and a mutation of an NUP can cause HD-like pathology. Therefore, we evaluated the NPC and nucleocytoplasmic transport in multiple models of HD, including mouse and fly models, neurons transfected with mHTT, HD iPSC-derived neurons, and human HD brain regions. These studies revealed severe mislocalization and aggregation of NUPs and defective nucleocytoplasmic transport. HD repeat-associated non-ATG (RAN) translation proteins also disrupted nucleocytoplasmic transport. Additionally, overexpression of NUPs and treatment with drugs that prevent aberrant NUP biology also mitigated this transport defect and neurotoxicity, providing future novel therapy targets.

Published
2017

20. Poly(GP) proteins are a useful pharmacodynamic marker for C9ORF72-associated amyotrophic lateral sclerosis

Author

Gendron, Tania F, Chew, Jeannie, Stankowski, Jeannette N, Hayes, Lindsey R, Zhang, Yong-Jie, Prudencio, Mercedes, Carlomagno, Yari, Daughrity, Lillian M, Jansen-West, Karen, Perkerson, Emilie A, O'Raw, Aliesha, Cook, Casey, Pregent, Luc, Belzil, Veronique, van Blitterswijk, Marka, Tabassian, Lilia J, Lee, Chris W, Yue, Mei, Tong, Jimei, Song, Yuping, Castanedes-Casey, Monica, Rousseau, Linda, Phillips, Virginia, Dickson, Dennis W, Rademakers, Rosa, Fryer, John D, Rush, Beth K, Pedraza, Otto, Caputo, Ana M, Desaro, Pamela, Palmucci, Carla, Robertson, Amelia, Heckman, Michael G, Diehl, Nancy N, Wiggs, Edythe, Tierney, Michael, Braun, Laura, Farren, Jennifer, Lacomis, David, Ladha, Shafeeq, Fournier, Christina N, McCluskey, Leo F, Elman, Lauren B, Toledo, Jon B, McBride, Jennifer D, Tiloca, Cinzia, Morelli, Claudia, Poletti, Barbara, Solca, Federica, Prelle, Alessandro, Wuu, Joanne, Jockel-Balsarotti, Jennifer, Rigo, Frank, Ambrose, Christine, Datta, Abhishek, Yang, Weixing, Raitcheva, Denitza, Antognetti, Giovanna, McCampbell, Alexander, Van Swieten, John C, Miller, Bruce L, Boxer, Adam L, Brown, Robert H, Bowser, Robert, Miller, Timothy M, Trojanowski, John Q, Grossman, Murray, Berry, James D, Hu, William T, Ratti, Antonia, Traynor, Bryan J, Disney, Matthew D, Benatar, Michael, Silani, Vincenzo, Glass, Jonathan D, Floeter, Mary Kay, Rothstein, Jeffrey D, Boylan, Kevin B, and Petrucelli, Leonard

Subjects
Clinical Research, Neurodegenerative, Brain Disorders, Acquired Cognitive Impairment, Dementia, Neurosciences, ALS, Rare Diseases, Clinical Trials and Supportive Activities, Genetics, Neurological, Adult, Aged, Amyotrophic Lateral Sclerosis, Animals, Biomarkers, Brain, C9orf72 Protein, Cell Line, Dinucleotide Repeats, Humans, Induced Pluripotent Stem Cells, Leukocytes, Mononuclear, Longitudinal Studies, Mice, Middle Aged, Neurons, Oligonucleotides, Antisense, Prognosis, RNA, Biological Sciences, Medical and Health Sciences
Abstract

There is no effective treatment for amyotrophic lateral sclerosis (ALS), a devastating motor neuron disease. However, discovery of a G4C2 repeat expansion in the C9ORF72 gene as the most common genetic cause of ALS has opened up new avenues for therapeutic intervention for this form of ALS. G4C2 repeat expansion RNAs and proteins of repeating dipeptides synthesized from these transcripts are believed to play a key role in C9ORF72-associated ALS (c9ALS). Therapeutics that target G4C2 RNA, such as antisense oligonucleotides (ASOs) and small molecules, are thus being actively investigated. A limitation in moving such treatments from bench to bedside is a lack of pharmacodynamic markers for use in clinical trials. We explored whether poly(GP) proteins translated from G4C2 RNA could serve such a purpose. Poly(GP) proteins were detected in cerebrospinal fluid (CSF) and in peripheral blood mononuclear cells from c9ALS patients and, notably, from asymptomatic C9ORF72 mutation carriers. Moreover, CSF poly(GP) proteins remained relatively constant over time, boding well for their use in gauging biochemical responses to potential treatments. Treating c9ALS patient cells or a mouse model of c9ALS with ASOs that target G4C2 RNA resulted in decreased intracellular and extracellular poly(GP) proteins. This decrease paralleled reductions in G4C2 RNA and downstream G4C2 RNA-mediated events. These findings indicate that tracking poly(GP) proteins in CSF could provide a means to assess target engagement of G4C2 RNA-based therapies in symptomatic C9ORF72 repeat expansion carriers and presymptomatic individuals who are expected to benefit from early therapeutic intervention.

Published
2017

21. Metabolic support of tumour-infiltrating regulatory T cells by lactic acid

Author

Watson, McLane J., Vignali, Paolo D. A., Mullett, Steven J., Overacre-Delgoffe, Abigail E., Peralta, Ronal M., Grebinoski, Stephanie, Menk, Ashley V., Rittenhouse, Natalie L., DePeaux, Kristin, Whetstone, Ryan D., Vignali, Dario A. A., Hand, Timothy W., Poholek, Amanda C., Morrison, Brett M., Rothstein, Jeffrey D., Wendell, Stacy G., and Delgoffe, Greg M.

Published
2021
Full Text
View/download PDF

22. C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins

Author

Zhang, Yong-Jie, Gendron, Tania F, Grima, Jonathan C, Sasaguri, Hiroki, Jansen-West, Karen, Xu, Ya-Fei, Katzman, Rebecca B, Gass, Jennifer, Murray, Melissa E, Shinohara, Mitsuru, Lin, Wen-Lang, Garrett, Aliesha, Stankowski, Jeannette N, Daughrity, Lillian, Tong, Jimei, Perkerson, Emilie A, Yue, Mei, Chew, Jeannie, Castanedes-Casey, Monica, Kurti, Aishe, Wang, Zizhao S, Liesinger, Amanda M, Baker, Jeremy D, Jiang, Jie, Lagier-Tourenne, Clotilde, Edbauer, Dieter, Cleveland, Don W, Rademakers, Rosa, Boylan, Kevin B, Bu, Guojun, Link, Christopher D, Dickey, Chad A, Rothstein, Jeffrey D, Dickson, Dennis W, Fryer, John D, and Petrucelli, Leonard

Subjects
Acquired Cognitive Impairment, Brain Disorders, Neurodegenerative, Dementia, Amyotrophic Lateral Sclerosis, Animals, Atrophy, Behavior, Animal, Brain, C9orf72 Protein, Carrier Proteins, DNA-Binding Proteins, Frontotemporal Dementia, Gene Expression, Guanine Nucleotide Exchange Factors, Humans, Inclusion Bodies, Mice, Mutation, Nerve Degeneration, Neurons, Primary Cell Culture, Proteins, Ubiquitinated Proteins, Neurosciences, Psychology, Cognitive Sciences, Neurology & Neurosurgery
Abstract

Neuronal inclusions of poly(GA), a protein unconventionally translated from G4C2 repeat expansions in C9ORF72, are abundant in patients with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) caused by this mutation. To investigate poly(GA) toxicity, we generated mice that exhibit poly(GA) pathology, neurodegeneration and behavioral abnormalities reminiscent of FTD and ALS. These phenotypes occurred in the absence of TDP-43 pathology and required poly(GA) aggregation. HR23 proteins involved in proteasomal degradation and proteins involved in nucleocytoplasmic transport were sequestered by poly(GA) in these mice. HR23A and HR23B similarly colocalized to poly(GA) inclusions in C9ORF72 expansion carriers. Sequestration was accompanied by an accumulation of ubiquitinated proteins and decreased xeroderma pigmentosum C (XPC) levels in mice, indicative of HR23A and HR23B dysfunction. Restoring HR23B levels attenuated poly(GA) aggregation and rescued poly(GA)-induced toxicity in neuronal cultures. These data demonstrate that sequestration and impairment of nuclear HR23 and nucleocytoplasmic transport proteins is an outcome of, and a contributor to, poly(GA) pathology.

Published
2016

24. G2C4 targeting antisense oligonucleotides potently mitigate TDP-43 dysfunction in human C9orf72 ALS/FTD induced pluripotent stem cell derived neurons

Author

Rothstein, Jeffrey D., primary, Baskerville, Victoria, additional, Rapuri, Sampath, additional, Mehlhop, Emma, additional, Jafar-Nejad, Paymaan, additional, Rigo, Frank, additional, Bennett, Frank, additional, Mizielinska, Sarah, additional, Isaacs, Adrian, additional, and Coyne, Alyssa N., additional

Published
2023
Full Text
View/download PDF

29. Safety and efficacy of ceftriaxone for amyotrophic lateral sclerosis: a multi-stage, randomised, double-blind, placebo-controlled trial

Author

Cudkowicz, Merit E, Titus, Sarah, Kearney, Marianne, Yu, Hong, Sherman, Alexander, Schoenfeld, David, Hayden, Douglas, Shui, Amy, Brooks, Benjamin, Conwit, Robin, Felsenstein, Donna, Greenblatt, David J, Keroack, Myles, Kissel, John T, Miller, Robert, Rosenfeld, Jeffrey, Rothstein, Jeffrey D, Simpson, Ericka, Tolkoff-Rubin, Nina, Zinman, Lorne, Shefner, Jeremy M, and Investigators, for the Ceftriaxone Study

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Clinical Trials and Supportive Activities, Clinical Research, Neurosciences, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Adult, Aged, Amyotrophic Lateral Sclerosis, Ceftriaxone, Double-Blind Method, Dyspnea, Female, Humans, Male, Middle Aged, Treatment Outcome, Ceftriaxone Study Investigators, Neurology & Neurosurgery, Clinical sciences
Abstract

BackgroundGlutamate excitotoxicity might contribute to the pathophysiology of amyotrophic lateral sclerosis. In animal models, decreased excitatory aminoacid transporter 2 (EAAT2) overexpression delays disease onset and prolongs survival, and ceftriaxone increases EAAT2 activity. We aimed to assess the safety and efficacy of ceftriaxone for amyotrophic lateral sclerosis in a combined phase 1, 2, and 3 clinical trial.MethodsThis three-stage randomised, double-blind, placebo-controlled study was done at 59 clinical sites in the USA and Canada between Sept 4, 2006, and July 30, 2012. Eligible adult patients had amyotrophic lateral sclerosis, a vital capacity of more than 60% of that predicted for age and height, and symptom duration of less than 3 years. In stages 1 (pharmacokinetics) and 2 (safety), participants were randomly allocated (2:1) to ceftriaxone (2 g or 4 g per day) or placebo. In stage 3 (efficacy), participants assigned to ceftriaxone in stage 2 received 4 g ceftriaxone, participants assigned to placebo in stage 2 received placebo, and new participants were randomly assigned (2:1) to 4 g ceftriaxone or placebo. Participants, family members, and site staff were masked to treatment assignment. Randomisation was done by a computerised randomisation sequence with permuted blocks of 3. Participants received 2 g ceftriaxone or placebo twice daily through a central venous catheter administered at home by a trained caregiver. To minimise biliary side-effects, participants assigned to ceftriaxone also received 300 mg ursodeoxycholic acid twice daily and those assigned to placebo received matched placebo capsules. The coprimary efficacy outcomes were survival and functional decline, measured as the slope of Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) scores. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00349622.FindingsStage 3 included 66 participants from stages 1 and 2 and 448 new participants. In total, 340 participants were randomly allocated to ceftriaxone and 173 to placebo. During stages 1 and 2, mean ALSFRS-R declined more slowly in participants who received 4 g ceftriaxone than in those on placebo (difference 0·51 units per month, 95% CI 0·02 to 1·00; p=0·0416), but in stage 3 functional decline between the treatment groups did not differ (0·09, -0·06 to 0·24; p=0·2370). No significant differences in survival between the groups were recorded in stage 3 (HR 0·90, 95% CI 0·71 to 1·15; p=0·4146). Gastrointestinal adverse events and hepatobiliary adverse events were more common in the ceftriaxone group than in the placebo group (gastrointestinal, 245 of 340 [72%] ceftriaxone vs 97 of 173 [56%] placebo, p=0·0004; hepatobiliary, 211 [62%] vs 19 [11%], p

Published
2014

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

Author

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, Marangi, Giuseppe, 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, Harms, Matthew B., Goldstein, David B., Shneider, Neil A., Goutman, Stephen, Simmons, Zachary, Miller, Timothy M., Chandran, Siddharthan, Pal, Suvankar, Manousakis, Georgios, Appel, Stanley H., Simpson, Ericka, Wang, Leo, Baloh, Robert H., Gibson, Summer, Bedlack, Richard, Lacomis, David, Sareen, Dhruv, Sherman, Alexander, Bruijn, Lucie, Penny, Michelle, Allen, Andrew S., Appel, Stanley, Bedlack, Richard 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, Steve, Dardiotis, Efthimios, Hornstein, Eran, MacGowan, Daniel J., Heiman-Patterson, Terry, Hammell, Molly G., Patsopoulos, Nikolaos A., Dubnau, Joshua, Nath, Avindra, Kaye, Julia, Finkbeiner, Steven, 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, 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, Ticozzi, Nicola, Gellera, Cinzia, Ratti, Antonia, Taroni, Franco, Lauria, Giuseppe, Verde, Federico, Fogh, Isabella, Tiloca, Cinzia, Comi, Giacomo P., Sorarù, Gianni, Cereda, Cristina, D’Alfonso, Sandra, Corrado, Lucia, De Marchi, Fabiola, Corti, Stefania, Ceroni, Mauro, Mazzini, Letizia, 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, Al Kheifat, Ahmad, Al-Chalabi, Ammar, Andersen, Peter, Basak, A. Nazli, Blair, Ian P., Chio, Adriano, Cooper-Knock, Jonathan, de Carvalho, Mamede, Dekker, Annelot, Drory, Vivian, Redondo, Alberto Garcia, Gotkine, Marc, Hardiman, Orla, Hide, Winston, Iacoangeli, Alfredo, Glass, Jonathan, Kenna, Kevin, Kiernan, Matthew, Kooyman, Maarten, Landers, John, McLaughlin, Russell, Middelkoop, Bas, Mill, Jonathan, Neto, Miguel Mitne, Moisse, Mattieu, Pardina, Jesus Mora, Morrison, Karen, Newhouse, Stephen, Pinto, Susana, Pulit, Sara, Robberecht, Wim, Shatunov, Aleksey, Shaw, Pamela, Shaw, Chris, Sproviero, William, Tazelaar, Gijs, van Damme, Philip, van den Berg, Leonard, van der Spek, Rick, van Eijk, Kristel, van Es, Michael, van Rheenen, Wouter, van Vugt, Joke, Veldink, Jan, Weber, Markus, Williams, Kelly L., Zatz, Mayana, Bauer, Denis C., Twine, Natalie A., Nicolas, Aude, Kenna, Kevin P., Renton, Alan E., Faghri, Faraz, Chia, Ruth, Dominov, Janice A., Kenna, Brendan J., Nalls, Mike A., Keagle, Pamela, Rivera, Alberto M., Murphy, Natalie A., van Vugt, Joke J.F.A., Geiger, Joshua T., Van der Spek, Rick A., Pliner, Hannah A., Shankaracharya, Smith, Bradley N., Topp, Simon D., Abramzon, Yevgeniya, Gkazi, Athina Soragia, Eicher, John D., Kenna, Aoife, Messina, Sonia, Simone, Isabella L., Ferrucci, Luigi, Moreno, Cristiane de Araujo Martins, Kamalakaran, Sitharthan, Musunuri, Rajeeva Lochan, Evani, Uday Shankar, Abhyankar, Avinash, Zody, Michael C., Wyman, Stacia K., LeNail, Alex, Van Eyk, Jennifer E., 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, Van Eijk, Kristel R., Moisse, Matthieu, McLaughlin, Russell L., Van Es, Michael A., Boylan, Kevin B., Van Blitterswijk, Marka, Morrison, Karen E., Mora, Jesús S., Drory, Vivian E., Shaw, Pamela J., Turner, Martin R., Talbot, Kevin, Fifita, Jennifer A., Nicholson, Garth A., Esteban-Pérez, Jesús, García-Redondo, Alberto, Rogaeva, Ekaterina, Zinman, Lorne, Cooper-Knock, Johnathan, Brice, Alexis, Goutman, Stephen A., Feldman, Eva L., Gibson, Summer B., Van Damme, Philip, Ludolph, Albert C., Andersen, Peter M., Weishaupt, Jochen H., Trojanowski, John Q., Brown, Robert H., Jr., 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.

Published
2018
Full Text
View/download PDF

31. Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis

Author

Kang, Shin H, Li, Ying, Fukaya, Masahiro, Lorenzini, Ileana, Cleveland, Don W, Ostrow, Lyle W, Rothstein, Jeffrey D, and Bergles, Dwight E

Subjects
Brain Disorders, Neurosciences, Rare Diseases, Stem Cell Research, Multiple Sclerosis, ALS, Stem Cell Research - Nonembryonic - Non-Human, Neurodegenerative, Genetics, Autoimmune Disease, Regenerative Medicine, Aetiology, 2.1 Biological and endogenous factors, Neurological, Amyotrophic Lateral Sclerosis, Animals, Animals, Newborn, Cell Proliferation, Cells, Cultured, Disease Models, Animal, Functional Laterality, Humans, Mice, Mice, Transgenic, Motor Cortex, Myelin Sheath, Nerve Degeneration, Nerve Fibers, Myelinated, Nerve Tissue Proteins, Oligodendroglia, Receptor, Platelet-Derived Growth Factor alpha, Regeneration, Spinal Cord, Survival Analysis, Psychology, Cognitive Sciences, Neurology & Neurosurgery
Abstract

Oligodendrocytes associate with axons to establish myelin and provide metabolic support to neurons. In the spinal cord of amyotrophic lateral sclerosis (ALS) mice, oligodendrocytes downregulate transporters that transfer glycolytic substrates to neurons and oligodendrocyte progenitors (NG2(+) cells) exhibit enhanced proliferation and differentiation, although the cause of these changes in oligodendroglia is unknown. We found extensive degeneration of gray matter oligodendrocytes in the spinal cord of SOD1 (G93A) ALS mice prior to disease onset. Although new oligodendrocytes were formed, they failed to mature, resulting in progressive demyelination. Oligodendrocyte dysfunction was also prevalent in human ALS, as gray matter demyelination and reactive changes in NG2(+) cells were observed in motor cortex and spinal cord of ALS patients. Selective removal of mutant SOD1 from oligodendroglia substantially delayed disease onset and prolonged survival in ALS mice, suggesting that ALS-linked genes enhance the vulnerability of motor neurons and accelerate disease by directly impairing the function of oligodendrocytes.

Published
2013

32. Molecularly defined cortical astroglia subpopulation modulates neurons via secretion of Norrin

Author

Miller, Sean J., Philips, Thomas, Kim, Namho, Dastgheyb, Raha, Chen, Zhuoxun, Hsieh, Yi-Chun, Daigle, J. Gavin, Datta, Malika, Chew, Jeannie, Vidensky, Svetlana, Pham, Jacqueline T., Hughes, Ethan G., Robinson, Michael B., Sattler, Rita, Tomer, Raju, Suk, Jung Soo, Bergles, Dwight E., Haughey, Norman, Pletnikov, Mikhail, Hanes, Justin, and Rothstein, Jeffrey D.

Published
2019
Full Text
View/download PDF

33. Creation of an open-access, mutation-defined fibroblast resource for neurological disease research.

Author

Wray, Selina, Self, Matthew, NINDS Parkinson's Disease iPSC Consortium, NINDS Huntington's Disease iPSC Consortium, NINDS ALS iPSC Consortium, Lewis, Patrick A, Taanman, Jan-Willem, Ryan, Natalie S, Mahoney, Colin J, Liang, Yuying, Devine, Michael J, Sheerin, Una-Marie, Houlden, Henry, Morris, Huw R, Healy, Daniel, Marti-Masso, Jose-Felix, Preza, Elisavet, Barker, Suzanne, Sutherland, Margaret, Corriveau, Roderick A, D'Andrea, Michael, Schapira, Anthony HV, Uitti, Ryan J, Guttman, Mark, Opala, Grzegorz, Jasinska-Myga, Barbara, Puschmann, Andreas, Nilsson, Christer, Espay, Alberto J, Slawek, Jaroslaw, Gutmann, Ludwig, Boeve, Bradley F, Boylan, Kevin, Stoessl, A Jon, Ross, Owen A, Maragakis, Nicholas J, Van Gerpen, Jay, Gerstenhaber, Melissa, Gwinn, Katrina, Dawson, Ted M, Isacson, Ole, Marder, Karen S, Clark, Lorraine N, Przedborski, Serge E, Finkbeiner, Steven, Rothstein, Jeffrey D, Wszolek, Zbigniew K, Rossor, Martin N, and Hardy, John

Subjects
NINDS Parkinson's Disease iPSC Consortium, NINDS Huntington's Disease iPSC Consortium, NINDS ALS iPSC Consortium, Cell Line, Fibroblasts, Humans, Nervous System Diseases, Biopsy, Immunohistochemistry, Cell Differentiation, Cell Proliferation, Mutation, Models, Genetic, Access to Information, Databases, Factual, Tissue Banks, Induced Pluripotent Stem Cells, Stem Cell Research - Induced Pluripotent Stem Cell - Human, Stem Cell Research - Induced Pluripotent Stem Cell, Genetics, Stem Cell Research, Neurosciences, Brain Disorders, Aetiology, 2.6 Resources and infrastructure (aetiology), 2.1 Biological and endogenous factors, Generic health relevance, Neurological, General Science & Technology
Abstract

Our understanding of the molecular mechanisms of many neurological disorders has been greatly enhanced by the discovery of mutations in genes linked to familial forms of these diseases. These have facilitated the generation of cell and animal models that can be used to understand the underlying molecular pathology. Recently, there has been a surge of interest in the use of patient-derived cells, due to the development of induced pluripotent stem cells and their subsequent differentiation into neurons and glia. Access to patient cell lines carrying the relevant mutations is a limiting factor for many centres wishing to pursue this research. We have therefore generated an open-access collection of fibroblast lines from patients carrying mutations linked to neurological disease. These cell lines have been deposited in the National Institute for Neurological Disorders and Stroke (NINDS) Repository at the Coriell Institute for Medical Research and can be requested by any research group for use in in vitro disease modelling. There are currently 71 mutation-defined cell lines available for request from a wide range of neurological disorders and this collection will be continually expanded. This represents a significant resource that will advance the use of patient cells as disease models by the scientific community.

Published
2012

34. Macrophage monocarboxylate transporter 1 promotes peripheral nerve regeneration after injury in mice

Author

Jha, Mithilesh Kumar, Passero, Joseph V., Rawat, Atul, Ament, Xanthe Heifetz, Yang, Fang, Vidensky, Svetlana, Collins, Samuel L., Horton, Maureen R., Hoke, Ahmet, Rutter, Guy A., Latremoliere, Alban, Rothstein, Jeffrey D., and Morrison, Brett M.

Subjects
Macrophages -- Physiological aspects -- Health aspects -- Genetic aspects, Peripheral nerve diseases -- Models -- Physiological aspects, Nervous system -- Regeneration, Health care industry
Abstract

Peripheral nerves have the capacity for regeneration, but the rate of regeneration is so slow that many nerve injuries lead to incomplete recovery and permanent disability for patients. Macrophages play a critical role in the peripheral nerve response to injury, contributing to both Wallerian degeneration and nerve regeneration, and their function has recently been shown to be dependent on intracellular metabolism. To date, the impact of their intracellular metabolism on peripheral nerve regeneration has not been studied. We examined conditional transgenic mice with selective ablation in macrophages of solute carrier family 16, member 1 (Slc16a1), which encodes monocarboxylate transporter 1 (MCT1), and found that MCT1 contributed to macrophage metabolism, phenotype, and function, specifically in regard to phagocytosis and peripheral nerve regeneration. Adoptive cell transfer of wild-type macrophages ameliorated the impaired nerve regeneration in macrophage-selective MCT1-null mice. We also developed a mouse model that overexpressed MCT1 in macrophages and found that peripheral nerves in these mice regenerated more rapidly than in control mice. Our study provides further evidence that MCT1 has an important biological role in macrophages and that manipulations of macrophage metabolism can enhance recovery from peripheral nerve injuries, for which there are currently no approved medical therapies., Introduction Recovery from peripheral nerve injury, which can occur as a result of trauma, surgical iatrogenesis, medications, or toxins, depends on a carefully orchestrated series of events within injured axons [...]

Published
2021
Full Text
View/download PDF

37. Genome-wide structural variant analysis identifies risk loci for non-Alzheimer’s dementias

Author

Kaivola, Karri, primary, Chia, Ruth, additional, Ding, Jinhui, additional, Rasheed, Memoona, additional, Fujita, Masashi, additional, Menon, Vilas, additional, Walton, Ronald L., additional, Collins, Ryan L., additional, Billingsley, Kimberley, additional, Brand, Harrison, additional, Talkowski, Michael, additional, Zhao, Xuefang, additional, Dewan, Ramita, additional, Stark, Ali, additional, Ray, Anindita, additional, Solaiman, Sultana, additional, Alvarez Jerez, Pilar, additional, Malik, Laksh, additional, Dawson, Ted M., additional, Rosenthal, Liana S., additional, Albert, Marilyn S., additional, Pletnikova, Olga, additional, Troncoso, Juan C., additional, Masellis, Mario, additional, Keith, Julia, additional, Black, Sandra E., additional, Ferrucci, Luigi, additional, Resnick, Susan M., additional, Tanaka, Toshiko, additional, Topol, Eric, additional, Torkamani, Ali, additional, Tienari, Pentti, additional, Foroud, Tatiana M., additional, Ghetti, Bernardino, additional, Landers, John E., additional, Ryten, Mina, additional, Morris, Huw R., additional, Hardy, John A., additional, Mazzini, Letizia, additional, D'Alfonso, Sandra, additional, Moglia, Cristina, additional, Calvo, Andrea, additional, Serrano, Geidy E., additional, Beach, Thomas G., additional, Ferman, Tanis, additional, Graff-Radford, Neill R., additional, Boeve, Bradley F., additional, Wszolek, Zbigniew K., additional, Dickson, Dennis W., additional, Chiò, Adriano, additional, Bennett, David A., additional, De Jager, Philip L., additional, Ross, Owen A., additional, Dalgard, Clifton L., additional, Gibbs, J. Raphael, additional, Traynor, Bryan J., additional, Scholz, Sonja W., additional, Soltis, Anthony R., additional, Viollet, Coralie, additional, Sukumar, Gauthaman, additional, Alba, Camille, additional, Lott, Nathaniel, additional, McGrath Martinez, Elisa, additional, Tuck, Meila, additional, Singh, Jatinder, additional, Bacikova, Dagmar, additional, Zhang, Xijun, additional, Hupalo, Daniel N., additional, Adeleye, Adelani, additional, Wilkerson, Matthew D., additional, Pollard, Harvey B., additional, Gan-Or, Ziv, additional, Rogaeva, Ekaterina, additional, Brice, Alexis, additional, Lesage, Suzanne, additional, Xiromerisiou, Georgia, additional, Canosa, Antonio, additional, Chio, Adriano, additional, Logroscino, Giancarlo, additional, Mora, Gabriele, additional, Krüger, Reijko, additional, May, Patrick, additional, Alcolea, Daniel, additional, Clarimon, Jordi, additional, Fortea, Juan, additional, Gonzalez-Aramburu, Isabel, additional, Infante, Jon, additional, Lage, Carmen, additional, Lleó, Alberto, additional, Pastor, Pau, additional, Sanchez-Juan, Pascual, additional, Brett, Francesca, additional, Aarsland, Dag, additional, Al-Sarraj, Safa, additional, Attems, Johannes, additional, Gentleman, Steve, additional, Hodges, Angela K., additional, Love, Seth, additional, McKeith, Ian G., additional, Morris, Christopher M., additional, Palmer, Laura, additional, Pickering-Brown, Stuart, additional, Thomas, Alan J., additional, Troakes, Claire, additional, Barrett, Matthew J., additional, Bekris, Lynn M., additional, Faber, Kelley, additional, Flanagan, Margaret E., additional, Goate, Alison, additional, Goldstein, David S., additional, Kaufmann, Horacio, additional, Kukull, Walter A., additional, Leverenz, James B., additional, Lopez, Grisel, additional, Mao, Qinwen, additional, Masliah, Eliezer, additional, Monuki, Edwin, additional, Newell, Kathy L., additional, Palma, Jose-Alberto, additional, Perkins, Matthew, additional, Renton, Alan E., additional, Scherzer, Clemens R., additional, Shakkottai, Vikram G., additional, Sidransky, Ellen, additional, Tayebi, Nahid, additional, Woltjer, Randy, additional, Baloh, Robert H., additional, Bowser, Robert, additional, Broach, James, additional, Camu, William, additional, Cooper-Knock, John, additional, Drepper, Carsten, additional, Drory, Vivian E., additional, Dunckley, Travis L., additional, Feldman, Eva, additional, Fratta, Pietro, additional, Gerhard, Glenn, additional, Gibson, Summer B., additional, Glass, Jonathan D., additional, Harms, Matthew B., additional, Heiman-Patterson, Terry D., additional, Jansson, Lilja, additional, Kirby, Janine, additional, Kwan, Justin, additional, Laaksovirta, Hannu, additional, Landi, Francesco, additional, Le Ber, Isabelle, additional, Lumbroso, Serge, additional, MacGowan, Daniel J.L., additional, Maragakis, Nicholas J., additional, Mouzat, Kevin, additional, Myllykangas, Liisa, additional, Orrell, Richard W., additional, Ostrow, Lyle W., additional, Pamphlett, Roger, additional, Pioro, Erik, additional, Pulst, Stefan M., additional, Ravits, John M., additional, Robberecht, Wim, additional, Rothstein, Jeffrey D., additional, Sendtner, Michael, additional, Shaw, Pamela J., additional, Sidle, Katie C., additional, Simmons, Zachary, additional, Stein, Thor, additional, Stone, David J., additional, Tienari, Pentti J., additional, Valori, Miko, additional, Van Damme, Philip, additional, Van Deerlin, Vivianna M., additional, Van Den Bosch, Ludo, additional, and Zinman, Lorne, additional

Published
2023
Full Text
View/download PDF

39. Messenger RNA oxidation occurs early in disease pathogenesis and promotes motor neuron degeneration in ALS.

Author

Chang, Yueming, Kong, Qiongman, Shan, Xiu, Tian, Guilian, Ilieva, Hristelina, Cleveland, Don W, Rothstein, Jeffrey D, Borchelt, David R, Wong, Philip C, and Lin, Chien-Liang Glenn

Subjects
Motor Cortex, Spinal Cord, Animals, Humans, Mice, Mice, Mutant Strains, Motor Neuron Disease, Nerve Degeneration, Superoxide Dismutase, RNA, Messenger, Oxidation-Reduction, Superoxide Dismutase-1, General Science & Technology
Abstract

BackgroundAccumulating evidence indicates that RNA oxidation is involved in a wide variety of neurological diseases and may be associated with neuronal deterioration during the process of neurodegeneration. However, previous studies were done in postmortem tissues or cultured neurons. Here, we used transgenic mice to demonstrate the role of RNA oxidation in the process of neurodegeneration.Methodology/principal findingsWe demonstrated that messenger RNA (mRNA) oxidation is a common feature in amyotrophic lateral sclerosis (ALS) patients as well as in many different transgenic mice expressing familial ALS-linked mutant copper-zinc superoxide dismutase (SOD1). In mutant SOD1 mice, increased mRNA oxidation primarily occurs in the motor neurons and oligodendrocytes of the spinal cord at an early, pre-symptomatic stage. Identification of oxidized mRNA species revealed that some species are more vulnerable to oxidative damage, and importantly, many oxidized mRNA species have been implicated in the pathogenesis of ALS. Oxidative modification of mRNA causes reduced protein expression. Reduced mRNA oxidation by vitamin E restores protein expression and partially protects motor neurons.Conclusion/significanceThese findings suggest that mRNA oxidation is an early event associated with motor neuron deterioration in ALS, and may be also a common early event preceding neuron degeneration in other neurological diseases.

Published
2008

41. G2C4 targeting antisense oligonucleotides potently mitigate TDP-43 dysfunction in human C9orf72 ALS/FTD induced pluripotent stem cell derived neurons.

Author

Rothstein, Jeffrey D., Baskerville, Victoria, Rapuri, Sampath, Mehlhop, Emma, Jafar-Nejad, Paymaan, Rigo, Frank, Bennett, Frank, Mizielinska, Sarah, Isaacs, Adrian, and Coyne, Alyssa N.

Subjects
*PLURIPOTENT stem cells, *INDUCED pluripotent stem cells, *ANTISENSE RNA, *OLIGONUCLEOTIDES, *AMYOTROPHIC lateral sclerosis, *MOTOR neuron diseases
Abstract

The G4C2 repeat expansion in the C9orf72 gene is the most common genetic cause of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Many studies suggest that dipeptide repeat proteins produced from this repeat are toxic, yet, the contribution of repeat RNA toxicity is under investigated and even less is known regarding the pathogenicity of antisense repeat RNA. Recently, two clinical trials targeting G4C2 (sense) repeat RNA via antisense oligonucleotide failed despite a robust decrease in sense-encoded dipeptide repeat proteins demonstrating target engagement. Here, in this brief report, we show that G2C4 antisense, but not G4C2 sense, repeat RNA is sufficient to induce TDP-43 dysfunction in induced pluripotent stem cell (iPSC) derived neurons (iPSNs). Unexpectedly, only G2C4, but not G4C2 sense strand targeting, ASOs mitigate deficits in TDP-43 function in authentic C9orf72 ALS/FTD patient iPSNs. Collectively, our data suggest that the G2C4 antisense repeat RNA may be an important therapeutic target and provide insights into a possible explanation for the recent G4C2 ASO clinical trial failure. [ABSTRACT FROM AUTHOR]

Published
2024
Full Text
View/download PDF

42. Genome-wide structural variant analysis identifies risk loci for non-Alzheimer’s dementias

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Luxembourg Institute of Health - LIH [research center], Fonds National de la Recherche - FnR [sponsor], Kaivola, Karri, Chia, Ruth, Ding, Jinhui, Rasheed, Memoona, Fujita, Masashi, Menon, Vilas, Walton, Ronald L., Collins, Ryan L., Billingsley, Kimberley, Brand, Harrison, Talkowski, Michael, Zhao, Xuefang, Dewan, Ramita, Stark, Ali, Ray, Anindita, Solaiman, Sultana, Alvarez Jerez, Pilar, Malik, Laksh, Dawson, Ted M., Rosenthal, Liana S., Albert, Marilyn S., Pletnikova, Olga, Troncoso, Juan C., Masellis, Mario, Keith, Julia, Black, Sandra E., Ferrucci, Luigi, Resnick, Susan M., Tanaka, Toshiko, Topol, Eric, Torkamani, Ali, Tienari, Pentti, Foroud, Tatiana M., Ghetti, Bernardino, Landers, John E., Ryten, Mina, Morris, Huw R., Hardy, John A., Mazzini, Letizia, D'Alfonso, Sandra, Moglia, Cristina, Calvo, Andrea, Serrano, Geidy E., Beach, Thomas G., Ferman, Tanis, Graff-Radford, Neill R., Boeve, Bradley F., Wszolek, Zbigniew K., Dickson, Dennis W., Chiò, Adriano, Bennett, David A., De Jager, Philip L., Ross, Owen A., Dalgard, Clifton L., Gibbs, J. Raphael, Traynor, Bryan J., Scholz, Sonja W., Soltis, Anthony R., Viollet, Coralie, Sukumar, Gauthaman, Alba, Camille, Lott, Nathaniel, McGrath Martinez, Elisa, Tuck, Meila, Singh, Jatinder, Bacikova, Dagmar, Zhang, Xijun, Hupalo, Daniel N., Adeleye, Adelani, Wilkerson, Matthew D., Pollard, Harvey B., Gan-Or, Ziv, Rogaeva, Ekaterina, Brice, Alexis, Lesage, Suzanne, Xiromerisiou, Georgia, Canosa, Antonio, Chio, Adriano, Logroscino, Giancarlo, Mora, Gabriele, Krüger, Rejko, May, Patrick, Alcolea, Daniel, Clarimon, Jordi, Fortea, Juan, Gonzalez-Aramburu, Isabel, Infante, Jon, Lage, Carmen, Lleó, Alberto, Pastor, Pau, Sanchez-Juan, Pascual, Brett, Francesca, Aarsland, Dag, Al-Sarraj, Safa, Attems, Johannes, Gentleman, Steve, Hodges, Angela K., Love, Seth, McKeith, Ian G., Morris, Christopher M., Palmer, Laura, Pickering-Brown, Stuart, Thomas, Alan J., Troakes, Claire, Barrett, Matthew J., Bekris, Lynn M., Faber, Kelley, Flanagan, Margaret E., Goate, Alison, Goldstein, David S., Kaufmann, Horacio, Kukull, Walter A., Leverenz, James B., Lopez, Grisel, Mao, Qinwen, Masliah, Eliezer, Monuki, Edwin, Newell, Kathy L., Palma, Jose-Alberto, Perkins, Matthew, Renton, Alan E., Scherzer, Clemens R., Shakkottai, Vikram G., Sidransky, Ellen, Tayebi, Nahid, Woltjer, Randy, Baloh, Robert H., Bowser, Robert, Broach, James, Camu, William, Cooper-Knock, John, Drepper, Carsten, Drory, Vivian E., Dunckley, Travis L., Feldman, Eva, Fratta, Pietro, Gerhard, Glenn, Gibson, Summer B., Glass, Jonathan D., Harms, Matthew B., Heiman-Patterson, Terry D., Jansson, Lilja, Kirby, Janine, Kwan, Justin, Laaksovirta, Hannu, Landi, Francesco, Le Ber, Isabelle, Lumbroso, Serge, MacGowan, Daniel J. L., Maragakis, Nicholas J., Mouzat, Kevin, Myllykangas, Liisa, Orrell, Richard W., Ostrow, Lyle W., Pamphlett, Roger, Pioro, Erik, Pulst, Stefan M., Ravits, John M., Robberecht, Wim, Rothstein, Jeffrey D., Sendtner, Michael, Shaw, Pamela J., Sidle, Katie C., Simmons, Zachary, Stein, Thor, Stone, David J., Tienari, Pentti J., Valori, Miko, Van Damme, Philip, Van Deerlin, Vivianna M., Van Den Bosch, Ludo, Zinman, Lorne, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Luxembourg Institute of Health - LIH [research center], Fonds National de la Recherche - FnR [sponsor], Kaivola, Karri, Chia, Ruth, Ding, Jinhui, Rasheed, Memoona, Fujita, Masashi, Menon, Vilas, Walton, Ronald L., Collins, Ryan L., Billingsley, Kimberley, Brand, Harrison, Talkowski, Michael, Zhao, Xuefang, Dewan, Ramita, Stark, Ali, Ray, Anindita, Solaiman, Sultana, Alvarez Jerez, Pilar, Malik, Laksh, Dawson, Ted M., Rosenthal, Liana S., Albert, Marilyn S., Pletnikova, Olga, Troncoso, Juan C., Masellis, Mario, Keith, Julia, Black, Sandra E., Ferrucci, Luigi, Resnick, Susan M., Tanaka, Toshiko, Topol, Eric, Torkamani, Ali, Tienari, Pentti, Foroud, Tatiana M., Ghetti, Bernardino, Landers, John E., Ryten, Mina, Morris, Huw R., Hardy, John A., Mazzini, Letizia, D'Alfonso, Sandra, Moglia, Cristina, Calvo, Andrea, Serrano, Geidy E., Beach, Thomas G., Ferman, Tanis, Graff-Radford, Neill R., Boeve, Bradley F., Wszolek, Zbigniew K., Dickson, Dennis W., Chiò, Adriano, Bennett, David A., De Jager, Philip L., Ross, Owen A., Dalgard, Clifton L., Gibbs, J. Raphael, Traynor, Bryan J., Scholz, Sonja W., Soltis, Anthony R., Viollet, Coralie, Sukumar, Gauthaman, Alba, Camille, Lott, Nathaniel, McGrath Martinez, Elisa, Tuck, Meila, Singh, Jatinder, Bacikova, Dagmar, Zhang, Xijun, Hupalo, Daniel N., Adeleye, Adelani, Wilkerson, Matthew D., Pollard, Harvey B., Gan-Or, Ziv, Rogaeva, Ekaterina, Brice, Alexis, Lesage, Suzanne, Xiromerisiou, Georgia, Canosa, Antonio, Chio, Adriano, Logroscino, Giancarlo, Mora, Gabriele, Krüger, Rejko, May, Patrick, Alcolea, Daniel, Clarimon, Jordi, Fortea, Juan, Gonzalez-Aramburu, Isabel, Infante, Jon, Lage, Carmen, Lleó, Alberto, Pastor, Pau, Sanchez-Juan, Pascual, Brett, Francesca, Aarsland, Dag, Al-Sarraj, Safa, Attems, Johannes, Gentleman, Steve, Hodges, Angela K., Love, Seth, McKeith, Ian G., Morris, Christopher M., Palmer, Laura, Pickering-Brown, Stuart, Thomas, Alan J., Troakes, Claire, Barrett, Matthew J., Bekris, Lynn M., Faber, Kelley, Flanagan, Margaret E., Goate, Alison, Goldstein, David S., Kaufmann, Horacio, Kukull, Walter A., Leverenz, James B., Lopez, Grisel, Mao, Qinwen, Masliah, Eliezer, Monuki, Edwin, Newell, Kathy L., Palma, Jose-Alberto, Perkins, Matthew, Renton, Alan E., Scherzer, Clemens R., Shakkottai, Vikram G., Sidransky, Ellen, Tayebi, Nahid, Woltjer, Randy, Baloh, Robert H., Bowser, Robert, Broach, James, Camu, William, Cooper-Knock, John, Drepper, Carsten, Drory, Vivian E., Dunckley, Travis L., Feldman, Eva, Fratta, Pietro, Gerhard, Glenn, Gibson, Summer B., Glass, Jonathan D., Harms, Matthew B., Heiman-Patterson, Terry D., Jansson, Lilja, Kirby, Janine, Kwan, Justin, Laaksovirta, Hannu, Landi, Francesco, Le Ber, Isabelle, Lumbroso, Serge, MacGowan, Daniel J. L., Maragakis, Nicholas J., Mouzat, Kevin, Myllykangas, Liisa, Orrell, Richard W., Ostrow, Lyle W., Pamphlett, Roger, Pioro, Erik, Pulst, Stefan M., Ravits, John M., Robberecht, Wim, Rothstein, Jeffrey D., Sendtner, Michael, Shaw, Pamela J., Sidle, Katie C., Simmons, Zachary, Stein, Thor, Stone, David J., Tienari, Pentti J., Valori, Miko, Van Damme, Philip, Van Deerlin, Vivianna M., Van Den Bosch, Ludo, and Zinman, Lorne

Abstract

We characterized the role of structural variants, a largely unexplored type of genetic variation, in two non-Alzheimer’s dementias, namely Lewy body dementia (LBD) and frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS). To do this, we applied an advanced structural variant calling pipeline (GATK-SV) to short-read whole-genome sequence data from 5,213 European-ancestry cases and 4,132 controls. We discovered, replicated, and validated a deletion in TPCN1 as a novel risk locus for LBD and detected the known structural variants at the C9orf72 and MAPT loci as associated with FTD/ALS. We also identified rare pathogenic structural variants in both LBD and FTD/ALS. Finally, we assembled a catalog of structural variants that can be mined for new insights into the pathogenesis of these understudied forms of dementia.

Published
2023

43. Prospective natural history study of C9orf72 ALS clinical characteristics and biomarkers

Author

Cammack, Alexander J., Atassi, Nazem, Hyman, Theodore, van den Berg, Leonard H., Harms, Matthew, Baloh, Robert H., Brown, Robert H., van Es, Michael A., Veldink, Jan H., de Vries, Balint S., Rothstein, Jeffrey D., Drain, Caroline, Jockel-Balsarotti, Jennifer, Malcolm, Amber, Boodram, Sonia, Salter, Amber, Wightman, Nicholas, Yu, Hong, Sherman, Alexander V., Esparza, Thomas J., McKenna-Yasek, Diane, Owegi, Margaret A., Douthwright, Catherine, McCampbell, Alexander, Ferguson, Toby, Cruchaga, Carlos, Cudkowicz, Merit, and Miller, Timothy M.

Published
2019
Full Text
View/download PDF

46. Oligodendroglia: metabolic supporters of neurons

Author

Philips, Thomas and Rothstein, Jeffrey D.

Subjects
Neural circuitry -- Health aspects, Glia -- Health aspects, Health care industry
Abstract

Oligodendrocytes are glial cells that populate the entire CNS after they have differentiated from oligodendrocyte progenitor cells. From birth onward, oligodendrocytes initiate wrapping of neuronal axons with a multilamellar lipid structure called myelin. Apart from their well-established function in action potential propagation, more recent data indicate that oligodendrocytes are essential for providing metabolic support to neurons. Oligodendrocytes transfer energy metabolites to neurons through cytoplasmic 'myelinic' channels and monocarboxylate transporters, which allow for the fast delivery of short-carbon-chain energy metabolites like pyruvate and lactate to neurons. These substrates are metabolized and contribute to ATP synthesis in neurons. This Review will discuss our current understanding of this metabolic supportive function of oligodendrocytes and its potential impact in human neurodegenerative disease and related animal models., Introduction Oligodendrocytes are the cells in the CNS that produce myelin, a multilamellar lipid structure that wraps around axons and ensures proper conduction of action potentials. Oligodendrocytes are derived from [...]

Published
2017
Full Text
View/download PDF

47. Amyotrophic Lateral Sclerosis Clinical Trials and Interpretation of Functional End Points and Fluid Biomarkers

Author

Shefner, Jeremy M., primary, Bedlack, Richard, additional, Andrews, Jinsy A., additional, Berry, James D., additional, Bowser, Robert, additional, Brown, Robert, additional, Glass, Jonathan D., additional, Maragakis, Nicholas J., additional, Miller, Timothy M., additional, Rothstein, Jeffrey D., additional, and Cudkowicz, Merit E., additional

Published
2022
Full Text
View/download PDF

49. Poly(ADP-ribose) promotes toxicity of C9ORF72 arginine-rich dipeptide repeat proteins

Author

Gao, Junli, primary, Mewborne, Quinlan T., additional, Girdhar, Amandeep, additional, Sheth, Udit, additional, Coyne, Alyssa N., additional, Punathil, Ritika, additional, Kang, Bong Gu, additional, Dasovich, Morgan, additional, Veire, Austin, additional, DeJesus Hernandez, Mariely, additional, Liu, Shuaichen, additional, Shi, Zheng, additional, Dafinca, Ruxandra, additional, Fouquerel, Elise, additional, Talbot, Kevin, additional, Kam, Tae-In, additional, Zhang, Yong-Jie, additional, Dickson, Dennis, additional, Petrucelli, Leonard, additional, van Blitterswijk, Marka, additional, Guo, Lin, additional, Dawson, Ted M., additional, Dawson, Valina L., additional, Leung, Anthony K. L., additional, Lloyd, Thomas E., additional, Gendron, Tania F., additional, Rothstein, Jeffrey D., additional, and Zhang, Ke, additional

Published
2022
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results