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

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.

Automated summary

Risk variants in the synaptic gene UNC13A are associated with increased risk of ALS and FTD. These variants lead to the inclusion of a cryptic exon in UNC13A when TDP-43 is depleted, resulting in the loss of UNC13A protein. Two common UNC13A polymorphisms strongly associated with ALS and FTD risk overlap with TDP-43 binding sites.