TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A.

1. Nature. 2022 Mar;603(7899):131-137. doi: 10.1038/s41586-022-04436-3. Epub 2022 Feb 23. TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A. Brown AL(#)(1), Wilkins OG(#)(1)(2), Keuss MJ(#)(1), Kargbo-Hill SE(#)(3), Zanovello M(1), Lee WC(1), Bampton A(4)(5), Lee FCY(1)(2), Masino L(2), Qi YA(6), Bryce-Smith S(1), Gatt A(4)(5), Hallegger M(1)(2), Fagegaltier D(7), Phatnani H(7); NYGC ALS Consortium; Newcombe J(8), Gustavsson EK(4)(9), Seddighi S(3)(10), Reyes JF(3), Coon SL(11), Ramos D(3)(6), Schiavo G(1)(12), Fisher EMC(1), Raj T(13)(14)(15)(16), Secrier M(17), Lashley T(4)(5), Ule J(1)(2)(18), Buratti E(19), Humphrey J(13)(14)(15)(16), Ward ME(20), Fratta P(21). Collaborators: Phatnani H, Kwan J, Sareen D, Broach JR, Simmons Z, Arcila-Londono X, Lee EB, Van Deerlin VM, Shneider NA, Fraenkel E, Ostrow LW, Baas F, Zaitlen N, Berry JD, Malaspina A, Fratta P, Cox GA, Thompson LM, Finkbeiner S, Dardiotis E, Miller TM, Chandran S, Pal S, Hornstein E, MacGowan DJ, Heiman-Patterson T, Hammell MG, Patsopoulos NA, Butovsky O, Dubnau J, Nath A, Bowser R, Harms M, Aronica E, Poss M, Phillips-Cremins J, Crary J, Atassi N, Lange DJ, Adams DJ, Stefanis L, Gotkine M, Baloh RH, Babu S, Raj T, Paganoni S, Shalem O, Smith C, Zhang B, Harris B, Broce I, Drory V, Ravits J, McMillan C, Menon V, Wu L, Altschuler S, Lerner Y, Sattler R, Van Keuren-Jensen K, Rozenblatt-Rosen O, Lindblad-Toh K, Nicholson K, Gregersen P, Lee JH, Koks S, Muljo S. Author information: (1)UCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK. (2)The Francis Crick Institute, London, UK. (3)National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA. (4)Queen Square Brain Bank, UCL Queen Square Institute of Neurology, University College London, London, UK. (5)Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, UK. (6)Center for Alzheimer's and Related Dementias, National Institutes of Health, Bethesda, MD, USA. (7)Center for Genomics of Neurodegenerative Disease, New York Genome Center (NYGC), New York, NY, USA. (8)NeuroResource, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, London, UK. (9)Great Ormond Street Institute of Child Health, Genetics and Genomic Medicine, University College London, London, UK. (10)Medical Scientist Training Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (11)Molecular Genomics Core, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA. (12)UK Dementia Research Institute, University College London, London, UK. (13)Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (14)Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (15)Department of Genetics and Genomic Sciences and Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (16)Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (17)Department of Genetics, Evolution and Environment, UCL Genetics Institute, University College London, London, UK. (18)Department of Molecular Biology and Nanobiotechnology, National Institute of Chemistry, Ljubljana, Slovenia. (19)Molecular Pathology Lab, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy. (20)National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA. wardme@nih.gov. (21)UCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK. p.fratta@ucl.ac.uk. (#)Contributed equally Erratum in Nature. 2024 Jul;631(8020):E7. doi: 10.1038/s41586-024-07577-9. Comment in Nature. 2022 Mar;603(7899):33-34. doi: 10.1038/d41586-022-00383-1. Med. 2022 Apr 8;3(4):226-227. doi: 10.1016/j.medj.2022.03.008. Trends Genet. 2022 Sep;38(9):889-891. doi: 10.1016/j.tig.2022.06.004. 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 g