TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A.
journal contributionposted on 2022-03-11, 12:54 authored by Anna-Leigh Brown, Oscar G Wilkins, Matthew J Keuss, Sarah E Hill, Matteo Zanovello, Weaverly Colleen Lee, Alexander Bampton, Flora CY Lee, Laura Masino, Yue A Qi, Sam Bryce-Smith, Ariana Gatt, Martina Hallegger, Delphine Fagegaltier, Hemali Phatnani, NYGC ALS Consortium, Jia Newcombe, Emil K Gustavsson, Sahba Seddighi, Joel F Reyes, Steven L Coon, Daniel Ramos, Giampietro Schiavo, Elizabeth MC Fisher, Towfique Raj, Maria Secrier, Tammaryn Lashley, Jernej Ule, Emanuele Buratti, Jack Humphrey, Michael E Ward, Pietro Fratta
Variants of UNC13A, a critical gene for synapse function, increase the risk of amyotrophic lateral sclerosis and frontotemporal dementia1-3, two related neurodegenerative diseases defined by mislocalization of the RNA-binding protein TDP-434,5. 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.