TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A
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s41586-022-04436-3.pdf
Description
Published version
Size
12.45 MB
Format
Adobe PDF
Checksum (MD5)
af93ced39310c7631587a5292b604440
Author(s)
Fraenkel, Ernest
Date Issued
2022
Journal
Nature
Publisher
Springer Science and Business Media LLC
Citation
Fraenkel, Ernest. 2022. "TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A." Nature, 603 (7899).
Version
Final published version
Abstract
AbstractVariants 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.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Terms of Use
Creative Commons Attribution 4.0 International license
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DOI of Published Version
https://doi.org/10.1038/S41586-022-04436-3
