TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A
Brown, Anna-Leigh; Wilkins, Oscar G; Keuss, Matthew J; Hill, Sarah E; Zanovello, Matteo; Lee, Weaverly Colleen; Bampton, Alexander; Lee, Flora C Y; Masino, Laura; Qi, Yue A; Bryce-Smith, Sam; Gatt, Ariana; Hallegger, Martina; Fagegaltier, Delphine; Phatnani, Hemali; Newcombe, Jia; Gustavsson, Emil K; Seddighi, Sahba; Reyes, Joel F; Coon, Steven L; Ramos, Daniel; Schiavo, Giampietro; Fisher, Elizabeth M C; Raj, Towfique; Secrier, Maria; Lashley, Tammaryn; Ule, Jernej; Buratti, Emanuele; Humphrey, Jack; Ward, Michael E; Fratta, Pietro; 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, Matthew; Aronica, Eleonora; 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; Lerner, Yossef; Sattler, Rita; Van Keuren-Jensen, Kendall; Rozenblatt-Rosen, Orit; Lindblad-Toh, Kerstin; Nicholson, Katharine; Gregersen, Peter; Lee, Jeong-Ho; Kokos, Sulev; Muljo, Stephen
Variants of UNC13A, a critical gene for synapse function, increase the risk of amyotrophic lateral sclerosis and frontotemporal dementia1-3, two related neurodegenerative diseases defined by mislocalization of the RNA-binding protein TDP-434,5. Here we show that TDP-43 depletion induces robust inclusion of a cryptic exon in UNC13A, resulting in nonsense-mediated decay and loss of UNC13A protein. Two common intronic UNC13A polymorphisms strongly associated with amyotrophic lateral sclerosis and frontotemporal dementia risk overlap with TDP-43 binding sites. These polymorphisms potentiate cryptic exon inclusion, both in cultured cells and in brains and spinal cords from patients with these conditions. Our findings, which demonstrate a genetic link between loss of nuclear TDP-43 function and disease, reveal the mechanism by which UNC13A variants exacerbate the effects of decreased TDP-43 function. They further provide a promising therapeutic target for TDP-43 proteinopathies.
PMID: 35197628
ISSN: 1476-4687
CID: 5428742
An integrated multi-omic analysis of iPSC-derived motor neurons from C9ORF72 ALS patients
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; Fraenkel, Ernest; Rothstein, Jeffrey D; Sareen, Dhruv; Svendsen, Clive N; Thompson, Leslie M; 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
Neurodegenerative diseases are challenging for systems biology because of the lack of reliable animal models or patient samples at early disease stages. Induced pluripotent stem cells (iPSCs) could address these challenges. We investigated DNA, RNA, epigenetics, and proteins in iPSC-derived motor neurons from patients with ALS carrying hexanucleotide expansions in C9ORF72. Using integrative computational methods combining all omics datasets, we identified novel and known dysregulated pathways. We used a C9ORF72 Drosophila model to distinguish pathways contributing to disease phenotypes from compensatory ones and confirmed alterations in some pathways in postmortem spinal cord tissue of patients with ALS. A different differentiation protocol was used to derive a separate set of C9ORF72 and control motor neurons. Many individual -omics differed by protocol, but some core dysregulated pathways were consistent. This strategy of analyzing patient-specific neurons provides disease-related outcomes with small numbers of heterogeneous lines and reduces variation from single-omics to elucidate network-based signatures.
PMCID:8554488
PMID: 34746695
ISSN: 2589-0042
CID: 5429252
Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis
Dewan, Ramita; Chia, Ruth; Ding, Jinhui; Hickman, Richard A; Stein, Thor D; Abramzon, Yevgeniya; Ahmed, Sarah; Sabir, Marya S; Portley, Makayla K; Tucci, Arianna; Ibáñez, Kristina; Shankaracharya, F N U; Keagle, Pamela; Rossi, Giacomina; Caroppo, Paola; Tagliavini, Fabrizio; Waldo, Maria L; Johansson, Per M; Nilsson, Christer F; Rowe, James B; Benussi, Luisa; Binetti, Giuliano; Ghidoni, Roberta; Jabbari, Edwin; Viollet, Coralie; Glass, Jonathan D; Singleton, Andrew B; Silani, Vincenzo; Ross, Owen A; Ryten, Mina; Torkamani, Ali; Tanaka, Toshiko; Ferrucci, Luigi; Resnick, Susan M; Pickering-Brown, Stuart; Brady, Christopher B; Kowal, Neil; Hardy, John A; Van Deerlin, Vivianna; Vonsattel, Jean Paul; Harms, Matthew B; Morris, Huw R; Ferrari, Raffaele; Landers, John E; Chiò, Adriano; Gibbs, J Raphael; Dalgard, Clifton L; Scholz, Sonja W; Traynor, Bryan J; Adeleye, Adelani; Alba, Camille; Bacikova, Dagmar; Hupalo, Daniel N; Martinez, Elisa McGrath; Pollard, Harvey B; Sukumar, Gauthaman; Soltis, Anthony R; Tuck, Meila; Zhang, Xijun; Wilkerson, Matthew D; Smith, Bradley N; Ticozzi, Nicola; Fallini, Claudia; Gkazi, Athina Soragia; Topp, Simon D; Kost, Jason; Scotter, Emma L; Kenna, Kevin P; Miller, Jack W; Tiloca, Cinzia; Vance, Caroline; Danielson, Eric W; Troakes, Claire; Colombrita, Claudia; Al-Sarraj, Safa; Lewis, Elizabeth A; King, Andrew; Calini, Daniela; Pensato, Viviana; Castellotti, Barbara; de Belleroche, Jacqueline; Baas, Frank; Ten Asbroek, Anneloor L M A; Sapp, Peter C; McKenna-Yasek, Diane; McLaughlin, Russell L; Polak, Meraida; Asress, Seneshaw; Esteban-Pérez, Jesús; Muñoz-Blanco, José Luis; Stevic, Zorica; D'Alfonso, Sandra; Mazzini, Letizia; Comi, Giacomo P; Del Bo, Roberto; Ceroni, Mauro; Gagliardi, Stella; Querin, Giorgia; Bertolin, Cinzia; van Rheenen, Wouter; Diekstra, Frank P; Rademakers, Rosa; van Blitterswijk, Marka; Boylan, Kevin B; Lauria, Giuseppe; Duga, Stefano; Corti, Stefania; Cereda, Cristina; Corrado, Lucia; Sorarù, Gianni; Williams, Kelly L; Nicholson, Garth A; Blair, Ian P; Leblond-Manry, Claire; Rouleau, Guy A; Hardiman, Orla; Morrison, Karen E; Veldink, Jan H; van den Berg, Leonard H; Al-Chalabi, Ammar; Pall, Hardev; Shaw, Pamela J; Turner, Martin R; Talbot, Kevin; Taroni, Franco; GarcÃa-Redondo, Alberto; Wu, Zheyang; Gellera, Cinzia; Ratti, Antonia; Brown, Robert H Jr; Shaw, Christopher E; Ambrose, John C; Arumugam, Prabhu; Baple, Emma L; Bleda, Marta; Boardman-Pretty, Freya; Boissiere, Jeanne M; Boustred, Christopher R; Brittain, H; Caulfield, Mark J; Chan, Georgia C; Craig, Clare E H; Daugherty, Louise C; de Burca, Anna; Devereau, Andrew; Elgar, Greg; Foulger, Rebecca E; Fowler, Tom; Furió-TarÃ, Pedro; Hackett, Joanne M; Halai, Dina; Hamblin, Angela; Henderson, Shirley; Holman, James E; Hubbard, Tim J P; Jackson, Rob; Jones, Louise J; Kasperaviciute, Dalia; Kayikci, Melis; Lahnstein, Lea; Lawson, Kay; Leigh, Sarah E A; Leong, Ivonne U S; Lopez, Javier F; Maleady-Crowe, Fiona; Mason, Joanne; McDonagh, Ellen M; Moutsianas, Loukas; Mueller, Michael; Murugaesu, Nirupa; Need, Anna C; Odhams, Chris A; Patch, Christine; Perez-Gil, Daniel; Polychronopoulos, Dimitris; Pullinger, John; Rahim, Tahrima; Rendon, Augusto; Riesgo-Ferreiro, Pablo; Rogers, Tim; Savage, Kevin; Sawant, Kushmita; Scott, Richard H; Siddiq, Afshan; Sieghart, Alexander; Smedley, Damian; Smith, Katherine R; Sosinsky, Alona; Spooner, William; Stevens, Helen E; Stuckey, Alexander; Sultana, Razvan; Thomas, Ellen R A; Thompson, Simon R; Tregidgo, Carolyn; Walsh, Emma; Watters, Sarah A; Welland, Matthew J; Williams, Eleanor; Witkowska, Katarzyna; Wood, Suzanne M; Zarowiecki, Magdalena; Arepalli, Sampath; Auluck, Pavan; Baloh, Robert H; Bowser, Robert; Brice, Alexis; Broach, James; Camu, William; Chiò, Adriano; Cooper-Knock, John; Corcia, Philippe; Drepper, Carsten; Drory, Vivian E; Dunckley, Travis L; Faghri, Faraz; Farren, Jennifer; Feldman, Eva; Floeter, Mary Kay; Fratta, Pietro; Gerhard, Glenn; Gibson, Summer B; Goutman, Stephen A; Heiman-Patterson, Terry D; Hernandez, Dena G; Hoover, Ben; Jansson, Lilja; Kamel, Freya; Kirby, Janine; Kowall, Neil W; Laaksovirta, Hannu; Landi, Francesco; Le Ber, Isabelle; Lumbroso, Serge; MacGowan, Daniel Jl; Maragakis, Nicholas J; Mora, Gabriele; Mouzat, Kevin; Myllykangas, Liisa; Nalls, Mike A; Orrell, Richard W; Ostrow, Lyle W; Pamphlett, Roger; Pioro, Erik; Pulst, Stefan M; Ravits, John M; Renton, Alan E; Robberecht, Wim; Robey, Ian; Rogaeva, Ekaterina; Rothstein, Jeffrey D; Sendtner, Michael; Shaw, Pamela J; Sidle, Katie C; Simmons, Zachary; Stone, David J; Tienari, Pentti J; Trojanowski, John Q; Troncoso, Juan C; Valori, Miko; Van Damme, Philip; Van Den Bosch, Ludo; Zinman, Lorne; Albani, Diego; Borroni, Barbara; Padovani, Alessandro; Bruni, Amalia; Clarimon, Jordi; Dols-Icardo, Oriol; Illán-Gala, Ignacio; Lleó, Alberto; Danek, Adrian; Galimberti, Daniela; Scarpini, Elio; Serpente, Maria; Graff, Caroline; Chiang, Huei-Hsin; Khoshnood, Behzad; Öijerstedt, Linn; Morris, Christopher M; Nacmias, Benedetta; Sorbi, Sandro; Nielsen, Jorgen E; Hjermind, Lynne E; Novelli, Valeria; Puca, Annibale A; Pastor, Pau; Alvarez, Ignacio; Diez-Fairen, Monica; Aguilar, Miquel; Perneczky, Robert; Diehl-Schimd, Janine; Rogaeva, Ekaterina; Rossi, Mina; Ruiz, Agustin; Boada, Mercè; Hernández, Isabel; Moreno-Grau, Sonia; Schlachetzki, Johannes C; Aarsland, Dag; Alba, Camille; Albert, Marilyn S; Al-Sarraj, Safa; Attems, Johannes; Bacikova, Dagmar; Barrett, Matthew J; Beach, Thomas G; Bekris, Lynn M; Bennett, David A; Besser, Lilah M; Bigio, Eileen H; Black, Sandra E; Boeve, Bradley F; Bohannan, Ryan C; Brett, Francesca; Brice, Alexis; Brunetti, Maura; Caraway, Chad A; Palma, Jose-Alberto; Calvo, Andrea; Canosa, Antonio; Clarimon, Jordi; Dickson, Dennis; Diez-Fairen, Monica; Duyckaerts, Charles; Faber, Kelley; Ferman, Tanis; Flanagan, Margaret E; Floris, Gianluca; Foroud, Tatiana M; Fortea, Juan; Gan-Or, Ziv; Gentleman, Steve; Ghetti, Bernardino; Gibbs, Jesse Raphael; Goate, Alison; Goldstein, David; González-Aramburu, Isabel; Graff-Radford, Neill R; Hodges, Angela K; Hu, Heng-Chen; Hupalo, Daniel; Infante, Jon; Iranzo, Alex; Kaiser, Scott M; Kaufmann, Horacio; Keith, Julia; Kim, Ronald C; Klein, Gregory; Krüger, Rejko; Kukull, Walter; Kuzma, Amanda; Lage, Carmen; Lesage, Suzanne; Lleó, Alberto; Leverenz, James B; Logroscino, Giancarlo; Lopez, Grisel; Love, Seth; Mao, Qinwen; Marti, Maria Jose; Martinez-McGrath, Elisa; Masellis, Mario; Masliah, Eliezer; May, Patrick; McKeith, Ian; Mesulam, Marek-Marsel; Monuki, Edwin S; Morris, Christopher M; Newell, Kathy L; Norcliffe-Kaufmann, Lucy; Palmer, Laura; Pastor, Pau; Perkins, Matthew; Pletnikova, Olga; Molina-Porcel, Laura; Renton, Alan E; Reynolds, Regina H; RodrÃguez-RodrÃguez, Eloy; Rogaeva, Ekaterina; Rohrer, Jonathan D; Sanchez-Juan, Pascual; Scherzer, Clemens R; Serrano, Geidy E; Shakkottai, Vikram; Sidransky, Ellen; Tayebi, Nahid; Thomas, Alan J; Tilley, Bension S; Troakes, Claire; Troncoso, Juan C; Walton, Ronald L; Woltjer, Randy; Wszolek, Zbigniew K; Xiromerisiou, Georgia; Zecca, Chiara; Phatnani, Hemali; Kwan, Justin; Sareen, Dhruv; Broach, James R; Simmons, Zachary; Arcila-Londono, Ximena; Lee, Edward B; 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; Aronica, Eleonora; 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; Amar, Khaled; Archibald, Neil; Bandmann, Oliver; Capps, Erica; Church, Alistair; Coebergh, Jan; Costantini, Alyssa; Critchley, Peter; Ghosh, Boyd Cp; Hu, Michele T M; Kobylecki, Christopher; Leigh, P Nigel; Mann, Carl; Massey, Luke A; Morris, Huw R; Nath, Uma; Pavese, Nicola; Paviour, Dominic; Sharma, Jagdish; Vaughan, Jenny
We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40-64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington's disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.
PMID: 33242422
ISSN: 1097-4199
CID: 5429222