In:
Nature, Springer Science and Business Media LLC, Vol. 603, No. 7899 ( 2022-03-03), p. 131-137
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.
Type of Medium:
Online Resource
ISSN:
0028-0836
,
1476-4687
DOI:
10.1038/s41586-022-04436-3
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2022
detail.hit.zdb_id:
120714-3
detail.hit.zdb_id:
1413423-8
SSG:
11
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