The Levy Library Blog

Article in the Spotlight: May 2022

Each month Levy Library showcases the achievements of Mount Sinai faculty and researchers by highlighting an article and its altmetrics. Altmetrics are alternative measures of impact that capture non-traditional data like abstract views, article downloads, and social media activity. Our altmetrics data is provided by the PlumX platform. 

This month we highlight TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A. This article was written in part by Jack Humphrey PhD, Dale Lange MD, Towfique Raj PhD, Daniel MacGowan MD, and John F. Crary MD, PhD.

ABSTRACT

Variants of UNC13A, a critical gene for synapse function, increase the risk of amyotrophic lateral sclerosis and frontotemporal dementia^1,2,3, 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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