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

Brown, Anna-Leigh, Wilkins, Oscar G, Keuss, Matthew J, Hill, Sarah E, Zanovello, Matteo, Lee, Weaverly Colleen, Bampton, Alexander, Lee, Flora CY, Masino, Laura, Qi, Yue A, Bryce-Smith, Sam, Gatt, Ariana, Hallegger, Martina, Fagegaltier, Delphine, Phatnani, Hemali, NYGC ALS Consortium, , Newcombe, Jia, Gustavsson, Emil K, Seddighi, Sahba, Reyes, Joel F, Coon, Steven L, Ramos, Daniel, Schiavo, Giampietro, Fisher, Elizabeth MC, Raj, Towfique, Secrier, Maria, Lashley, Tammaryn, Ule, Jernej, Buratti, Emanuele, Humphrey, Jack, Ward, Michael E, Fratta, Pietro (February 2022) TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A. Nature, 603 (7899). pp. 131-137. ISSN 0028-0836

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Abstract

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.

Item Type:	Paper
Subjects:	diseases & disorders > neurodegenerative diseases > ALS bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > exons > exon splicing Investigative techniques and equipment > assays > RNA-seq organs, tissues, organelles, cell types and functions > cell types and functions > cell types > stem cells organs, tissues, organelles, cell types and functions > cell types and functions > cell types > stem cells organs, tissues, organelles, cell types and functions > cell types and functions > cell types > stem cells
CSHL Authors:	Hammell, Molly
Communities:	CSHL labs > Hammell M. lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	23 February 2022
Date Deposited:	14 Apr 2022 19:00
Last Modified:	14 Apr 2022 19:00
PMCID:	PMC8891020
URI:	https://repository.cshl.edu/id/eprint/40584

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