Version history

{
  "pmid": "35197628",
  "doi": "10.1038/s41586-022-04436-3",
  "abstract": "1. Nature. 2022 Mar;603(7899):131-137. doi: 10.1038/s41586-022-04436-3. Epub 2022\n Feb 23.\n\nTDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A.\n\nBrown AL(#)(1), Wilkins OG(#)(1)(2), Keuss MJ(#)(1), Kargbo-Hill SE(#)(3), \nZanovello M(1), Lee WC(1), Bampton A(4)(5), Lee FCY(1)(2), Masino L(2), Qi \nYA(6), Bryce-Smith S(1), Gatt A(4)(5), Hallegger M(1)(2), Fagegaltier D(7), \nPhatnani H(7); NYGC ALS Consortium; Newcombe J(8), Gustavsson EK(4)(9), Seddighi \nS(3)(10), Reyes JF(3), Coon SL(11), Ramos D(3)(6), Schiavo G(1)(12), Fisher \nEMC(1), Raj T(13)(14)(15)(16), Secrier M(17), Lashley T(4)(5), Ule J(1)(2)(18), \nBuratti E(19), Humphrey J(13)(14)(15)(16), Ward ME(20), Fratta P(21).\n\nCollaborators: Phatnani H, Kwan J, Sareen D, Broach JR, Simmons Z, \nArcila-Londono X, Lee EB, Van Deerlin VM, Shneider NA, Fraenkel E, Ostrow LW, \nBaas F, Zaitlen N, Berry JD, Malaspina A, Fratta P, Cox GA, Thompson LM, \nFinkbeiner S, Dardiotis E, Miller TM, Chandran S, Pal S, Hornstein E, MacGowan \nDJ, Heiman-Patterson T, Hammell MG, Patsopoulos NA, Butovsky O, Dubnau J, Nath \nA, Bowser R, Harms M, Aronica E, Poss M, Phillips-Cremins J, Crary J, Atassi N, \nLange DJ, Adams DJ, Stefanis L, Gotkine M, Baloh RH, Babu S, Raj T, Paganoni S, \nShalem O, Smith C, Zhang B, Harris B, Broce I, Drory V, Ravits J, McMillan C, \nMenon V, Wu L, Altschuler S, Lerner Y, Sattler R, Van Keuren-Jensen K, \nRozenblatt-Rosen O, Lindblad-Toh K, Nicholson K, Gregersen P, Lee JH, Koks S, \nMuljo S.\n\nAuthor information:\n(1)UCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular \nDiseases, UCL Queen Square Institute of Neurology, UCL, London, UK.\n(2)The Francis Crick Institute, London, UK.\n(3)National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, \nUSA.\n(4)Queen Square Brain Bank, UCL Queen Square Institute of Neurology, University \nCollege London, London, UK.\n(5)Department of Neurodegenerative Disease, UCL Queen Square Institute of \nNeurology, University College London, London, UK.\n(6)Center for Alzheimer's and Related Dementias, National Institutes of Health, \nBethesda, MD, USA.\n(7)Center for Genomics of Neurodegenerative Disease, New York Genome Center \n(NYGC), New York, NY, USA.\n(8)NeuroResource, Department of Neuroinflammation, UCL Queen Square Institute of \nNeurology, London, UK.\n(9)Great Ormond Street Institute of Child Health, Genetics and Genomic Medicine, \nUniversity College London, London, UK.\n(10)Medical Scientist Training Program, Johns Hopkins University School of \nMedicine, Baltimore, MD, USA.\n(11)Molecular Genomics Core, Eunice Kennedy Shriver National Institute of Child \nHealth and Human Development, NIH, Bethesda, MD, USA.\n(12)UK Dementia Research Institute, University College London, London, UK.\n(13)Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn \nSchool of Medicine at Mount Sinai, New York, NY, USA.\n(14)Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at \nMount Sinai, New York, NY, USA.\n(15)Department of Genetics and Genomic Sciences and Icahn Institute for Data \nScience and Genomic Technology, Icahn School of Medicine at Mount Sinai, New \nYork, NY, USA.\n(16)Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine \nat Mount Sinai, New York, NY, USA.\n(17)Department of Genetics, Evolution and Environment, UCL Genetics Institute, \nUniversity College London, London, UK.\n(18)Department of Molecular Biology and Nanobiotechnology, National Institute of \nChemistry, Ljubljana, Slovenia.\n(19)Molecular Pathology Lab, International Centre for Genetic Engineering and \nBiotechnology (ICGEB), Trieste, Italy.\n(20)National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, \nUSA. wardme@nih.gov.\n(21)UCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular \nDiseases, UCL Queen Square Institute of Neurology, UCL, London, UK. \np.fratta@ucl.ac.uk.\n(#)Contributed equally\n\nErratum in\n    Nature. 2024 Jul;631(8020):E7. doi: 10.1038/s41586-024-07577-9.\n\nComment in\n    Nature. 2022 Mar;603(7899):33-34. doi: 10.1038/d41586-022-00383-1.\n    Med. 2022 Apr 8;3(4):226-227. doi: 10.1016/j.medj.2022.03.008.\n    Trends Genet. 2022 Sep;38(9):889-891. doi: 10.1016/j.tig.2022.06.004.\n\nVariants of UNC13A, a critical gene for synapse function, increase the risk of \namyotrophic lateral sclerosis and frontotemporal dementia1-3, two related \nneurodegenerative diseases defined by mislocalization of the RNA-binding protein \nTDP-434,5. Here we show that TDP-43 depletion induces robust inclusion of a \ncryptic exon in UNC13A, resulting in nonsense-mediated decay and loss of UNC13A \nprotein. Two common intronic UNC13A polymorphisms strongly associated with \namyotrophic lateral sclerosis and frontotemporal dementia risk overlap with \nTDP-43 binding sites. These polymorphisms potentiate cryptic exon \ninclusion, both in cultured cells and in brains and spinal cords from patients \nwith these conditions. Our findings, which demonstrate a g",
  "journal": "Nature",
  "year": 2022,
  "authors": "Brown AL, Wilkins OG, Keuss MJ, Kargbo-Hill SE, Zanovello M, Lee WC, Bampton A, Lee FCY, Masino L, Qi YA",
  "url": "https://pubmed.ncbi.nlm.nih.gov/35197628",
  "external_ids": {
    "doi": "10.1038/s41586-022-04436-3",
    "pmid": "35197628"
  },
  "citation_count": 1,
  "domain": "neurodegeneration"
}