Common ALS/FTD risk variants in UNC13A exacerbate its cryptic splicing and loss upon TDP-43 mislocalization
Common ALS/FTD risk variants in UNC13A exacerbate its cryptic splicing and loss upon TDP-43 mislocalization
Abstract Variants within the UNC13A gene have long been known to increase risk of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two related neurodegenerative diseases defined by mislocalization of the RNA-binding protein TDP-43. Here, we show that TDP-43 depletion induces robust inclusion of a cryptic exon (CE) within UNC13A, a critical synaptic gene, resulting in nonsense-mediated decay and protein loss. Strikingly, two common polymorphisms strongly associated with ALS/FTD risk directly alter TDP-43 binding within the CE or downstream intron, increasing CE inclusion in cultured cells and in patient brains. Our findings, which are the first to demonstrate a genetic link specifically between loss of TDP-43 nuclear function and disease, reveal both the mechanism by which UNC13A variants exacerbate the effects of decreased nuclear TDP-43 function, and provide a promising therapeutic target for TDP-43 proteinopathies. One-Sentence SummaryShared ALS/FTD risk variants increase the sensitivity of a cryptic exon in the synaptic gene UNC13A to TDP-43 depletion.
Lee Flora C.Y.、Brown Anna-Leigh、Zanovello Matteo、Qi Yue A.、Bryce-Smith Sam、Bampton Alexander、Gatt Ariana、NYGC ALS Consortium、Lashley Tammaryn、Raj Towfique、Ule Jernej、Buratti Emanuele、Wilkins Oscar G.、Lee Weaverly Colleen、Ward Michael E.、Secrier Maria、Hill Sarah E.、Fratta Pietro、Masino Laura、Humphrey Jack、Phatnani Hemali、Fisher Elizabeth M.C.、Keuss Matthew J.、Schiavo Giampietro
Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology||The Francis Crick InstituteDepartment of Neuromuscular Diseases, UCL Queen Square Institute of NeurologyDepartment of Neuromuscular Diseases, UCL Queen Square Institute of NeurologyNational Institute of Neurological Disorders and StrokeDepartment of Neuromuscular Diseases, UCL Queen Square Institute of NeurologyQueen Square Brain Bank, UCL Queen Square Institute of Neurology, University College London||Queen Square Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College LondonQueen Square Brain Bank, UCL Queen Square Institute of Neurology, University College London||Queen Square Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College LondonThe NYGC ALS Consortium is detailed in supplemental acknowledgmentsQueen Square Brain Bank, UCL Queen Square Institute of Neurology, University College London||Queen Square Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College LondonNash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai||Ronald M. Loeb Center for Alzheimer?ˉs Disease, Icahn School of Medicine at Mount Sinai||Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai||Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount SinaiDepartment of Neuromuscular Diseases, UCL Queen Square Institute of Neurology||The Francis Crick Institute||Department of Molecular Biology and Nanobiotechnology, National Institute of ChemistryMolecular Pathology Lab, International Centre for Genetic Engineering and Biotechnology (ICGEB)Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology||The Francis Crick InstituteDepartment of Neuromuscular Diseases, UCL Queen Square Institute of NeurologyNational Institute of Neurological Disorders and StrokeDepartment of Genetics, Evolution and Environment, UCL Genetics Institute, University College LondonNational Institute of Neurological Disorders and StrokeDepartment of Neuromuscular Diseases, UCL Queen Square Institute of NeurologyThe Francis Crick InstituteNash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai||Ronald M. Loeb Center for Alzheimer?ˉs Disease, Icahn School of Medicine at Mount Sinai||Department of Genetics and Genomic Sciences & Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai||Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount SinaiCenter for Genomics of Neurodegenerative Disease, New York Genome Center (NYGC)Department of Neuromuscular Diseases, UCL Queen Square Institute of NeurologyDepartment of Neuromuscular Diseases, UCL Queen Square Institute of NeurologyDepartment of Neuromuscular Diseases, UCL Queen Square Institute of Neurology||Nash Family Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai
神经病学、精神病学基础医学分子生物学
Lee Flora C.Y.,Brown Anna-Leigh,Zanovello Matteo,Qi Yue A.,Bryce-Smith Sam,Bampton Alexander,Gatt Ariana,NYGC ALS Consortium,Lashley Tammaryn,Raj Towfique,Ule Jernej,Buratti Emanuele,Wilkins Oscar G.,Lee Weaverly Colleen,Ward Michael E.,Secrier Maria,Hill Sarah E.,Fratta Pietro,Masino Laura,Humphrey Jack,Phatnani Hemali,Fisher Elizabeth M.C.,Keuss Matthew J.,Schiavo Giampietro.Common ALS/FTD risk variants in UNC13A exacerbate its cryptic splicing and loss upon TDP-43 mislocalization[EB/OL].(2025-03-28)[2025-08-16].https://www.biorxiv.org/content/10.1101/2021.04.02.438170.点此复制
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