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

doi:10.1038/s41586-022-04436-3

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Article

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

Nature - 1 Mar 2022

Brown Anna-Leigh, Wilkins Oscar G, Keuss Matthew J, Hill Sarah E, Zanovello Matteo, Lee Weaverly Colleen, Bampton Alexander, Lee Flora C Y, Masino Laura, Qi Yue A, Bryce-Smith Sam, Gatt Ariana, Hallegger Martina, Fagegaltier Delphine, Phatnani Hemali, Newcombe Jia, Gustavsson Emil K, Seddighi Sahba, Reyes Joel F, Coon Steven L, Ramos Daniel, Schiavo Giampietro, Fisher Elizabeth M C, Raj Towfique, Secrier Maria, Lashley Tammaryn, Ule Jernej, Buratti Emanuele, Humphrey Jack, Ward Michael E, Fratta Pietro

Abstract excerpt

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...

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PMID: 35197628
DOI: 10.1038/s41586-022-04436-3
PMCID: PMC8891020

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