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

Abstract

<jats:title>Abstract</jats:title><jats:p>Variants of <jats:italic>UNC13A</jats:italic>, a critical gene for synapse function, increase the risk of amyotrophic lateral sclerosis and frontotemporal dementia<jats:sup>1–3</jats:sup>, two related neurodegenerative diseases defined by mislocalization of the RNA-binding protein TDP-43<jats:sup>4,5</jats:sup>. Here we show that TDP-43 depletion induces robust inclusion of a cryptic exon in <jats:italic>UNC13A</jats:italic>, resulting in nonsense-mediated decay and loss of UNC13A protein. Two common intronic <jats:italic>UNC13A</jats:italic> 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 <jats:italic>UNC13A</jats:italic> variants exacerbate the effects of decreased TDP-43 function. They further provide a promising therapeutic target for TDP-43 proteinopathies.</jats:p>