作者
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, 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
发表日期
2022/3/3
期刊
Nature
卷号
603
期号
7899
页码范围
131-137
出版商
Nature Publishing Group UK
简介
Variants of UNC13A, a critical gene for synapse function, increase the risk of amyotrophic lateral sclerosis and frontotemporal dementia, –, two related neurodegenerative diseases defined by mislocalization of the RNA-binding protein TDP-43,. 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 …
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