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337 results on '"Rothstein, Jeffrey D"'

4. 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
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5. 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
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6. 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
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7. 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
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8. 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
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9. 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
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14. 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
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15. 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
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16. 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
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20. 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
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23. 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
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24. 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

Published
2017
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26. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport

Author

Zhang, Ke, Donnelly, Christopher J., Haeusler, Aaron R., Grima, Jonathan C., Machamer, James B., Steinwald, Peter, Daley, Elizabeth L., Miller, Sean J., Cunningham, Kathleen M., Vidensky, Svetlana, Gupta, Saksham, Thomas, Michael A., Hong, Ingie, Chiu, Shu-Ling, Huganir, Richard L., Ostrow, Lyle W., Matunis, Michael J., Wang, Jiou, Sattler, Rita, Lloyd, Thomas E., and Rothstein, Jeffrey D.

Subjects
Cytoplasm -- Genetic aspects, Trinucleotide repeats -- Research, Biological transport -- Genetic aspects, Genetic research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

The hexanucleotide repeat expansion (HRE) GGGGCC ([G.sub.4][C.sub.2]) in C9orf72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recent studies support an HRE RNA gain-of-function mechanism of neurotoxicity, and we previously identified protein interactors for the [G.sub.4][C.sub.2] RNA including RanGAP1. A candidate-based genetic screen in Drosophila expressing 30 [G.sub.4][C.sub.2] repeats identified RanGAP (Drosophila orthologue of human RanGAP1), a key regulator of nucleocytoplasmic transport, as a potent suppressor of neurodegeneration. Enhancing nuclear import or suppressing nuclear export of proteins also suppresses neurodegeneration. RanGAP physically interacts with HRE RNA and is mislocalized in HRE-expressing flies, neurons from C9orf72 ALS patient-derived induced pluripotent stem cells (iPSC-derived neurons), and in C9orf72 ALS patient brain tissue. Nuclear import is impaired as a result of HRE expression in the fly model and in C9orf72 iPSC-derived neurons, and these deficits are rescued by small molecules and antisense oligonucleotides targeting the HRE G-quadruplexes. Nucleocytoplasmic transport defects may be a fundamental pathway for ALS and FTD that is amenable to pharmacotherapeutic intervention., The [G.sub.4][C.sub.2] HRE in the C9orf72 gene is found in as many as 40% of familial ALS and FTD cases, with additional reports in other neurodegenerative diseases (1-3). C9orf72 HRE-induced [...]

Published
2015
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30. C9orf72 nucleotide repeat structures initiate molecular cascades of disease

Author

Haeusler, Aaron R., Donnelly, Christopher J., Periz, Goran, Simko, Eric A.J., Shaw, Patrick G., Kim, Min-Sik, Maragakis, Nicholas J., Troncoso, Juan C., Pandey, Akhilesh, Sattler, Rita, Rothstein, Jeffrey D., and Wang, Jiou

Subjects
Nucleotide sequencing -- Research, Molecular genetics -- Research, Genetic research, DNA sequencing -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

A hexanucleotide repeat expansion (HRE), [(GGGGCC).sub.n], in C9orf72 is the most common genetic cause of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we identify a molecular mechanism by which structural polymorphism of the HRE leads to ALS/FTD pathology and defects. The hRe forms DNA and RNA G-quadruplexes with distinct structures and promotes RNA* DNA hybrids (R-loops). The structural polymorphism causes a repeat-length-dependent accumulation of transcripts aborted in the hRe region. These transcribed repeats bind to ribonucleoproteins in a conformation-dependent manner. Specifically, nucleolin, an essential nucleolar protein, preferentially binds the HRE G-quadruplex, and patient cells show evidence of nucleolar stress. Our results demonstrate that distinct C9orf72 HRE structural polymorphism at both DNA and RNA levels initiates molecular cascades leading to ALS/FTD pathologies, and provide the basis for a mechanistic model for repeat-associated neurodegenerative diseases., Nucleotide repeat elements, including microsatellites and short tandem repeats, are common in eukaryotic genomes (1). Recently, a hexanucleotide repeat expansion (HRE), [(GGGGCC).sub.n], in a noncoding region of C9orf72 was linked [...]

Published
2014
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38. 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., and Katz, Jonathan

Abstract

Background: Coformulated sodium phenylbutyrate/taurursodiol (PB/TURSO) was shown to prolong survival and slow functional decline in amyotrophic lateral sclerosis (ALS).Objective: Determine whether PB/TURSO prolonged tracheostomy/ventilation-free survival and/or reduced first hospitalisation in participants with ALS in the CENTAUR trial.Methods: Adults 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.Results: Risk 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.Conclusions: Early PB/TURSO prolonged tracheostomy/PAV-free survival and delayed first hospitalisation in ALS.Trial Registration Number: NCT03127514; NCT03488524. [ABSTRACT FROM AUTHOR]

Published
2022
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40. Oligodendroglia metabolically support axons and contribute to neurodegeneration

Author

Lee, Youngjin, Morrison, Brett M., Li, Yun, Lengacher, Sylvain, Farah, Mohamed H., Hoffman, Paul N., Liu, Yiting, Tsingalia, Akivaga, Jin, Lin, Zhang, Ping-Wu, Pellerin, Luc, Magistretti, Pierre J., and Rothstein, Jeffrey D.

Subjects
Metabolism -- Physiological aspects, Oligodendroglia -- Physiological aspects, Nervous system -- Degeneration, Axons -- Physiological aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Oligodendroglia support axon survival and function through mechanisms independent of myelination, and their dysfunction leads to axon degeneration in several diseases. The cause of this degeneration has not been determined, but lack of energy metabolites such as glucose or lactate has been proposed. Lactate is transported exclusively by monocarboxylate transporters, and changes to these transporters alter lactate production and use. Here we show that the most abundant lactate transporter in the central nervous system, monocarboxylate transporter 1 (MCT1, also known as SLC16A1), is highly enriched within oligodendroglia and that disruption of this transporter produces axon damage and neuron loss in animal and cell culture models. In addition, this same transporter is reduced in patients with, and in mouse models of, amyotrophic lateral sclerosis, suggesting a role for oligodendroglial MCT1 in pathogenesis. The role of oligodendroglia in axon function and neuron survival has been elusive; this study defines a new fundamental mechanism by which oligodendroglia support neurons and axons., Oligodendroglia promote rapid conduction of action potentials by ensheathing central nervous system (CNS) axons with myelin. Oligodendrocyte diseases, such as multiple sclerosis and leukodystrophies, have demonstrated demyelination and axon degeneration [...]

Published
2012
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41. Nuclear Pore Dysfunction in Neurodegeneration.

Author

Spead, Olivia, Zaepfel, Benjamin L, and Rothstein, Jeffrey D

Abstract

The nuclear pore complex (NPC) is a large multimeric structure that is interspersed throughout the membrane of the nucleus and consists of at least 33 protein components. Individual components cooperate within the nuclear pore to facilitate selective passage of materials between the nucleus and cytoplasm while simultaneously performing pore-independent roles throughout the cell. NPC dysfunction is a hallmark of neurodegenerative disorders including Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS). NPC components can become mislocalized or altered in expression in neurodegeneration. These alterations in NPC structure are often detrimental to the neuronal function and ultimately lead to neuronal loss. This review highlights the importance of nucleocytoplasmic transport and NPC integrity and how dysfunction of such may contribute to neurodegeneration. [ABSTRACT FROM AUTHOR]

Published
2022
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42. Identification of Therapeutic Targets for Amyotrophic Lateral Sclerosis Using PandaOmics – An AI-Enabled Biological Target Discovery Platform.

Author

Pun, Frank W., Liu, Bonnie Hei Man, Long, Xi, Leung, Hoi Wing, Leung, Geoffrey Ho Duen, Mewborne, Quinlan T., Gao, Junli, Shneyderman, Anastasia, Ozerov, Ivan V., Wang, Ju, Ren, Feng, Aliper, Alexander, Bischof, Evelyne, Izumchenko, Evgeny, Guan, Xiaoming, Zhang, Ke, Lu, Bai, Rothstein, Jeffrey D., Cudkowicz, Merit E., and Zhavoronkov, Alex

Subjects
ARTIFICIAL intelligence, AMYOTROPHIC lateral sclerosis, RESEARCH funding
Abstract

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease with ill-defined pathogenesis, calling for urgent developments of new therapeutic regimens. Herein, we applied PandaOmics, an AI-driven target discovery platform, to analyze the expression profiles of central nervous system (CNS) samples (237 cases; 91 controls) from public datasets, and direct iPSC-derived motor neurons (diMNs) (135 cases; 31 controls) from Answer ALS. Seventeen high-confidence and eleven novel therapeutic targets were identified and will be released onto ALS.AI (http://als.ai/). Among the proposed targets screened in the c9ALS Drosophila model, we verified 8 unreported genes (KCNB2 , KCNS3 , ADRA2B , NR3C1 , P2RY14 , PPP3CB , PTPRC , and RARA) whose suppression strongly rescues eye neurodegeneration. Dysregulated pathways identified from CNS and diMN data characterize different stages of disease development. Altogether, our study provides new insights into ALS pathophysiology and demonstrates how AI speeds up the target discovery process, and opens up new opportunities for therapeutic interventions. [ABSTRACT FROM AUTHOR]

Published
2022
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43. Nuclear pore complexes - a doorway to neural injury in neurodegeneration.

Author

Coyne, Alyssa N. and Rothstein, Jeffrey D.

Abstract

The genetic underpinnings and end-stage pathological hallmarks of neurodegenerative diseases are increasingly well defined, but the cellular pathophysiology of disease initiation and propagation remains poorly understood, especially in sporadic forms of these diseases. Altered nucleocytoplasmic transport is emerging as a prominent pathomechanism of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis, Alzheimer disease, frontotemporal dementia and Huntington disease. The nuclear pore complex (NPC) and interactions between its individual nucleoporin components and nuclear transport receptors regulate nucleocytoplasmic transport, as well as genome organization and gene expression. Specific nucleoporin abnormalities have been identified in sporadic and familial forms of neurodegenerative disease, and these alterations are thought to contribute to disrupted nucleocytoplasmic transport. The specific nucleoporins and nucleocytoplasmic transport proteins that have been linked to different neurodegenerative diseases are partially distinct, suggesting that NPC injury contributes to the cellular specificity of neurodegenerative disease and could be an early initiator of the pathophysiological cascades that underlie neurodegenerative disease. This concept is consistent with the fact that rare genetic mutations in some nucleoporins cause cell-type-specific neurological disease. In this Review, we discuss nucleoporin and NPC disruptions and consider their impact on cellular function and the pathophysiology of neurodegenerative disease. [ABSTRACT FROM AUTHOR]

Published
2022
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46. β-Lactam antibiotics offer neuroprotection by increasing glutamate transporter expression

Author

Rothstein, Jeffrey D., Patel, Sarjubhai, Regan, Melissa R., Haenggeli, Christine, Huang, Yanhua H., Bergles, Dwight E., Jin, Lin, Dykes Hoberg, Margaret, Vidensky, Svetlana, Chung, Dorothy S., Toan, Shuy Vang, Bruijn, Lucie I., Su, Zao-zhong, Gupta, Pankaj, and Fisher, Paul B.

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Jeffrey D. Rothstein (corresponding author) [1, 2]; Sarjubhai Patel [1]; Melissa R. Regan [1]; Christine Haenggeli [1]; Yanhua H. Huang [2]; Dwight E. Bergles [2]; Lin Jin [1]; Margaret [...]

Published
2005
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47. Retrograde viral delivery of IGF-1 prolongs survival in a mouse ALS model

Author

Kaspar, Brian K., Llado, Jeronia, Sherkat, Nushin, Rothstein, Jeffrey D., and Gage, Fred H.

Subjects
Amyotrophic lateral sclerosis -- Care and treatment -- Research, Gene therapy -- Research -- Technology application, Science and technology, Technology application, Care and treatment, Research
Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive, lethal neuromuscuLar disease that is associated with the degeneration of spinal and brainstem motor neurons, leading to atrophy of limb, axial, and respiratory muscles. The cause of ALS is unknown, and there is no effective therapy. Neurotrophic factors are candidates for therapeutic evaluation in ALS. Although chronic delivery of molecules to the central nervous system has proven difficult, we recently discovered that adeno-associated virus can be retrogradely transported efficiently from muscle to motor neurons of the spinal cord. We report that insulin-Like growth factor 1 prolongs life and delays disease progression, even when delivered at the time of overt disease symptoms., Overexpression of superoxide dismutase-1 (SOD1) gene mutations in mice and rats recapitulates the clinical and pathological characteristics of amyotrophic lateral sclerosis (ALS) in humans, in which motor neurons (MNs) degenerate [...]

Published
2003

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