TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13AMore about Open Access at the Crick
Authors listAnna-Leigh Brown Oscar Wilkins Matthew J Keuss Sarah E Hill Matteo Zanovello Weaverly Colleen Lee Alexander Bampton Flora 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
Toggle all authors (32)
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.
Issue number 7899