Brown, Anna-Leigh;
Wilkins, Oscar G;
Keuss, Matthew J;
Hill, Sarah E;
Zanovello, Matteo;
Lee, Weaverly Colleen;
Bampton, Alexander;
... Fratta, Pietro; + view all
(2022)
TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A.
Nature
, 603
pp. 131-137.
10.1038/s41586-022-04436-3.
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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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