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

Article

关键词: GENOME-WIDE ASSOCIATION;    FRONTOTEMPORAL DEMENTIA;    READ ALIGNMENT;    GENE;    QUANTIFICATION;    DISEASE;    VISUALIZATION;    POLYMORPHISM;    REPRESSION;    FRAMEWORK;   

DOI  :  10.1038/s41586-022-04436-3

来源: SCIE

【 摘 要 】

Risk variants for ALS and FTD in the synaptic gene UNC13A increase the expression of an UNC13A cryptic exon in neurons with TDP-43 depletion. 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.

【 授权许可】

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