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Here we show that TDP-43 depletion induces robust inclusion of a cryptic exon in\n                    <jats:italic>UNC13A<\/jats:italic>\n                    , resulting in nonsense-mediated decay and loss of UNC13A protein. Two common intronic\n                    <jats:italic>UNC13A<\/jats:italic>\n                    polymorphisms strongly associated with amyotrophic lateral sclerosis and frontotemporal dementia risk overlap with TDP-43 binding sites. These\u00a0polymorphisms\u00a0potentiate cryptic exon inclusion,\u00a0both in cultured cells and in\u00a0brains 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\n                    <jats:italic>UNC13A<\/jats:italic>\n                    variants exacerbate the effects of decreased TDP-43 function. They further provide a promising therapeutic target for TDP-43 proteinopathies.\n                  <\/jats:p>","DOI":"10.1038\/s41586-022-04436-3","type":"journal-article","created":{"date-parts":[[2022,2,23]],"date-time":"2022-02-23T12:04:19Z","timestamp":1645617859000},"page":"131-137","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":576,"title":["TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A"],"prefix":"10.1038","volume":"603","author":[{"given":"Anna-Leigh","family":"Brown","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oscar G.","family":"Wilkins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J.","family":"Keuss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8499-7455","authenticated-orcid":false,"given":"Sarah E.","family":"Kargbo-Hill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Zanovello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weaverly Colleen","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Bampton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flora C. 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