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Publication Detail
TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A
  • Publication Type:
    Journal article
  • Authors:
    Brown A-L, Wilkins OG, Keuss MJ, Hill SE, Zanovello M, Lee WC, Bampton A, Lee FCY, Masino L, Qi YA, Bryce-Smith S, Gatt A, Hallegger M, Fagegaltier D, Phatnani H, NYGC ALS Consortium , Newcombe J, Gustavsson EK, Seddighi S, Reyes JF, Coon SL, Ramos D, Schiavo G, Fisher EMC, Raj T, Secrier M, Lashley T, Ule J, Buratti E, Humphrey J, Ward ME, Fratta P
  • Publisher:
    Springer Science and Business Media LLC
  • Publication date:
    02/2022
  • Pagination:
    131, 137
  • Journal:
    Nature
  • Volume:
    603
  • Medium:
    Print-Electronic
  • Status:
    Published
  • Country:
    England
  • PII:
    10.1038/s41586-022-04436-3
  • Language:
    English
  • Keywords:
    Amyotrophic lateral sclerosis, Neurodegeneration
  • Notes:
    © 2022 Springer Nature Limited. This article is licensed under a Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/).
Abstract
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 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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Department of Neuromuscular Diseases
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Department of Neuromuscular Diseases
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