@article{5fbf2b9416d9494888471825b3254cb8,
title = "TDP-43 represses cryptic exon inclusion in the FTD–ALS gene UNC13A",
abstract = "A hallmark pathological feature of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the depletion of RNA-binding protein TDP-43 from the nucleus of neurons in the brain and spinal cord1. A major function of TDP-43 is as a repressor of cryptic exon inclusion during RNA splicing2–4. Single nucleotide polymorphisms in UNC13A are among the strongest hits associated with FTD and ALS in human genome-wide association studies5,6, but how those variants increase risk for disease is unknown. Here we show that TDP-43 represses a cryptic exon-splicing event in UNC13A. Loss of TDP-43 from the nucleus in human brain, neuronal cell lines and motor neurons derived from induced pluripotent stem cells resulted in the inclusion of a cryptic exon in UNC13A mRNA and reduced UNC13A protein expression. The top variants associated with FTD or ALS risk in humans are located in the intron harbouring the cryptic exon, and we show that they increase UNC13A cryptic exon splicing in the face of TDP-43 dysfunction. Together, our data provide a direct functional link between one of the strongest genetic risk factors for FTD and ALS (UNC13A genetic variants), and loss of TDP-43 function.",
author = "Ma, {X. Rosa} and Mercedes Prudencio and Yuka Koike and Vatsavayai, {Sarat C.} and Garam Kim and Fred Harbinski and Adam Briner and Rodriguez, {Caitlin M.} and Caiwei Guo and Tetsuya Akiyama and Schmidt, {H. Broder} and Cummings, {Beryl B.} and Wyatt, {David W.} and Katherine Kurylo and Georgiana Miller and Shila Mekhoubad and Nathan Sallee and Gemechu Mekonnen and Laura Ganser and Rubien, {Jack D.} and Karen Jansen-West and Cook, {Casey N.} and Sarah Pickles and Bj{\"o}rn Oskarsson and Graff-Radford, {Neill R.} and Boeve, {Bradley F.} and Knopman, {David S.} and Petersen, {Ronald C.} and Dickson, {Dennis W.} and James Shorter and Sua Myong and Green, {Eric M.} and Seeley, {William W.} and Leonard Petrucelli and Gitler, {Aaron D.}",
note = "Funding Information: This work was supported by NIH grants R35NS097263(10) (A.D.G.), R35NS097273(17) (L.P.), U54NS123743 (A.D.G., L.P., M.P. and W.W.S.), P01NS084974 (L.P.), R01NS104437 (W.W.S.), RF1NS120992 (M.P.), F32 NS116208-02 (C.M.R.), T32 GM007231 (G. Mekonnen), 2T32AG047126-06A1 (T.A.), F32GM139268 (L.G.), RF1AG071326 (S. Myong.), RF1NS113636 (S. Myong), the Robert Packard Center for ALS Research at Johns Hopkins (L.P., J.S. and A.D.G.), P30AG06267 (R.C.P.), U01AG006786 (R.C.P.), 2T32HG000044-21 NIHGRI training grant (X.R.M.), the Brain Rejuvenation Project of the Wu Tsai Neurosciences Institute (A.D.G.), Target ALS (J.S.), Amyotrophic Lateral Sclerosis Association (J.S.), and the Office of the Assistant Secretary of Defense for Health Affairs through the Amyotrophic Lateral Sclerosis Research Program (W81XWH-20-1-0242 to J.S.). G.K. is supported by a fellowship from the Stanford Knight-Hennessy Scholars Program. A.B. is supported by a Fulbright Future Scholarship. Y.K. is supported by Milton Safenowitz Postdoctoral Fellowship Program from the Amyotrophic Lateral Sclerosis Association (21-PDF-582). S.P. is supported by a BrightFocus ADR Grant (A2020279F). T.A. is supported by a fellowship from the Takeda Science Foundation. The UCSF Neurodegenerative Disease Brain Bank receives funding support from NIH grants P30AG062422, P01AG019724, U01AG057195 and U19AG063911, as well as the Rainwater Charitable Foundation and the Bluefield Project to Cure FTD. Some of the computing for this project was performed on the Sherlock cluster. We would like to thank Stanford University and the Stanford Research Computing Center for providing computational resources and support that contributed to these research results. Funding Information: This work was supported by NIH grants R35NS097263(10) (A.D.G.), R35NS097273(17) (L.P.), U54NS123743 (A.D.G., L.P., M.P. and W.W.S.), P01NS084974 (L.P.), R01NS104437 (W.W.S.), RF1NS120992 (M.P.), F32 NS116208-02 (C.M.R.), T32 GM007231 (G.?Mekonnen), 2T32AG047126-06A1 (T.A.), F32GM139268 (L.G.), RF1AG071326 (S.?Myong.), RF1NS113636 (S.?Myong), the Robert Packard Center for ALS Research at Johns Hopkins (L.P., J.S. and A.D.G.), P30AG06267 (R.C.P.), U01AG006786 (R.C.P.), 2T32HG000044-21 NIHGRI training grant (X.R.M.), the Brain Rejuvenation Project of the Wu Tsai Neurosciences Institute (A.D.G.), Target ALS (J.S.), Amyotrophic Lateral Sclerosis Association (J.S.), and the Office of the Assistant Secretary of Defense for Health Affairs through the Amyotrophic Lateral Sclerosis Research Program (W81XWH-20-1-0242 to J.S.). G.K. is supported by a fellowship from the Stanford Knight-Hennessy Scholars Program. A.B. is supported by a Fulbright Future Scholarship. Y.K. is supported by Milton Safenowitz Postdoctoral Fellowship Program from the Amyotrophic Lateral Sclerosis Association (21-PDF-582). S.P. is supported by a BrightFocus ADR Grant (A2020279F). T.A. is supported by a fellowship from the Takeda Science Foundation. The UCSF Neurodegenerative Disease Brain Bank receives funding support from NIH grants P30AG062422, P01AG019724, U01AG057195 and U19AG063911, as well as the Rainwater Charitable Foundation and the Bluefield Project to Cure FTD. Some of the computing for this project was performed on the Sherlock cluster. We would like to thank Stanford University and the Stanford Research Computing Center for providing computational resources and support that contributed to these research results. Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
month = mar,
day = "3",
doi = "10.1038/s41586-022-04424-7",
language = "English (US)",
volume = "603",
pages = "124--130",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7899",
}