TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A
Anna‐Leigh Brown(National Hospital for Neurology and Neurosurgery), Oscar G. Wilkins(The Francis Crick Institute), Matthew J. Keuss(National Hospital for Neurology and Neurosurgery), Sarah E. Hill(National Institute of Neurological Disorders and Stroke), Matteo Zanovello(National Hospital for Neurology and Neurosurgery), Weaverly Colleen Lee(National Hospital for Neurology and Neurosurgery), Alexander Bampton(National Hospital for Neurology and Neurosurgery), Flora Lee(The Francis Crick Institute), Laura Masino(The Francis Crick Institute), Yue Qi(National Institutes of Health), Sam Bryce-Smith(National Hospital for Neurology and Neurosurgery), Ariana Gatt(National Hospital for Neurology and Neurosurgery), Martina Hallegger(The Francis Crick Institute), Delphine Fagegaltier(New York Genome Center), Hemali Phatnani(New York Genome Center), Hemali Phatnani(New York Genome Center), Justin Kwan(Temple University), Dhruv Sareen(Cedars-Sinai Medical Center), James R. Broach(Pennsylvania State University), Zachary Simmons(Pennsylvania State University), Ximena Arcila-Londono(Henry Ford Health System), Edward B. Lee(University of Pennsylvania), Vivianna M. Van Deerlin(University of Pennsylvania), Neil A. Shneider(Columbia University), Ernest Fraenkel(Massachusetts Institute of Technology), Lyle W. Ostrow(Johns Hopkins University), Frank Baas(Leiden University Medical Center), Noah Zaitlen(University of California, San Francisco), James D. Berry(Harvard University), Andrea Malaspina(Queen Mary University of London), Pietro Fratta(MRC Prion Unit), Gregory A. Cox(Jackson Laboratory), Leslie M. Thompson(University of California, Irvine), Steven Finkbeiner(Gladstone Institutes), Efthimios Dardiotis(University of Thessaly), Timothy M. Miller(Washington University in St. Louis), Siddharthan Chandran(Mott MacDonald (United Kingdom)), Suvankar Pal(Mott MacDonald (United Kingdom)), Eran Hornstein(Weizmann Institute of Science), Daniel J. MacGowan(Icahn School of Medicine at Mount Sinai), Terry Heiman‐Patterson(Temple University), Molly Hammell(Cold Spring Harbor Laboratory), Nikolaos A. Patsopoulos(Brigham and Women's Hospital), Oleg Butovsky(Brigham and Women's Hospital), Josh Dubnau(Stony Brook University), Avindra Nath(National Institute of Neurological Disorders and Stroke), Robert Bowser(Barrow Neurological Institute), Matthew B. Harms(Columbia University), Eleonora Aronica(Amsterdam UMC Location University of Amsterdam), Mary Poss(Pennsylvania State University), Jennifer E. Phillips‐Cremins(New York Stem Cell Foundation), John F. Crary(Allen Institute for Brain Science), Nazem Atassi(Harvard University), Dale J. Lange(Hospital for Special Surgery), Darius J. Adams(Morristown Medical Center), Leonidas Stefanis(Biomedical Research Foundation of the Academy of Athens), Marc Gotkine(Hadassah Medical Center), Robert H. Baloh, Suma Babu(Massachusetts General Hospital), Towfique Raj(Allen Institute for Brain Science), Sabrina Paganoni(Harvard University), Ophir Shalem(Children's Hospital of Philadelphia), Colin Smith(University of Edinburgh), Bin Zhang(Icahn School of Medicine at Mount Sinai), Brent T. Harris(Georgetown University), Iris Broce(University of California, San Francisco), Vivian E. Drory(Tel Aviv University), John Ravits(University of California San Diego), Corey T. McMillan(University of Pennsylvania), Vilas Menon(Columbia University Irving Medical Center), Lani F. Wu(University of California, San Francisco), Steven J. Altschuler(University of California, San Francisco), Yossef Lerner, Rita Sattler(Barrow Neurological Institute), Kendall Van Keuren‐Jensen(Translational Genomics Research Institute), Orit Rozenblatt–Rosen(Broad Institute), Kerstin Lindblad‐Toh(Broad Institute), Katharine Nicholson(Massachusetts General Hospital), Peter K. Gregersen(Northwell Health), Jeong‐Ho Lee(Korea Advanced Institute of Science and Technology), Sulev Kõks(Perron Institute for Neurological and Translational Science), Stephen Muljo(National Institute of Allergy and Infectious Diseases), Jia Newcombe(National Hospital for Neurology and Neurosurgery), Emil K. Gustavsson(Great Ormond Street Hospital), Sahba Seddighi(Johns Hopkins University), Joel F. Reyes(National Institute of Neurological Disorders and Stroke), Steven L. Coon(Eunice Kennedy Shriver National Institute of Child Health and Human Development), Daniel M. Ramos(National Institutes of Health), Giampietro Schiavo(UK Dementia Research Institute), Elizabeth Fisher(National Hospital for Neurology and Neurosurgery), Towfique Raj(Allen Institute for Brain Science), Maria Secrier(University College London), Tammaryn Lashley(National Hospital for Neurology and Neurosurgery), Jernej Ule(The Francis Crick Institute), Emanuele Buratti(International Centre for Genetic Engineering and Biotechnology), Jack Humphrey(Allen Institute for Brain Science), Michael E. Ward(National Institute of Neurological Disorders and Stroke), Pietro Fratta(MRC Prion Unit)
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Abstract
Abstract Variants of UNC13A , a critical gene for synapse function, increase the risk of amyotrophic lateral sclerosis and frontotemporal dementia 1–3 , two related neurodegenerative diseases defined by mislocalization of the RNA-binding protein TDP-43 4,5 . 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 genetic link between loss of nuclear TDP-43 function and disease, reveal the mechanism by which UNC13A variants exacerbate the effects of decreased TDP-43 function. They further provide a promising therapeutic target for TDP-43 proteinopathies.
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