TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A

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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Cited by papers we hold 5

• A fluid biomarker reveals loss of TDP-43 splicing repression in presymptomatic ALS–FTD · 2024
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• The era of cryptic exons: implications for ALS-FTD · 2023
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• Stage-specific control of oligodendrocyte survival and morphogenesis by TDP-43 · 2022
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• Maximizing CRISPRi efficacy and accessibility with dual-sgRNA libraries and optimal effectors · 2022
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• TDP-43 represses cryptic exon inclusion in the FTD–ALS gene UNC13A · 2022
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