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

Authors :
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
Kwan, Justin
Sareen, Dhruv
Broach, James R.
Simmons, Zachary
Arcila-Londono, Ximena
Lee, Edward B.
Van Deerlin, Vivianna M.
Shneider, Neil A.
Fraenkel, Ernest
Ostrow, Lyle W.
Baas, Frank
Zaitlen, Noah
Berry, James D.
Malaspina, Andrea
Fratta, Pietro
Cox, Gregory A.
Thompson, Leslie M.
Finkbeiner, Steve
Dardiotis, Efthimios
Miller, Timothy M.
Chandran, Siddharthan
Pal, Suvankar
Hornstein, Eran
MacGowan, Daniel J.
Heiman-Patterson, Terry
Hammell, Molly G.
Patsopoulos, Nikolaos. A.
Butovsky, Oleg
Dubnau, Joshua
Nath, Avindra
Bowser, Robert
Harms, Matthew
Aronica, Eleonora
Poss, Mary
Phillips-Cremins, Jennifer
Crary, John
Atassi, Nazem
Lange, Dale J.
Adams, Darius J.
Stefanis, Leonidas
Gotkine, Marc
Baloh, Robert H.
Babu, Suma
Raj, Towfique
Paganoni, Sabrina
Shalem, Ophir
Smith, Colin
Zhang, Bin
Harris, Brent
Broce, Iris
Drory, Vivian
Ravits, John
McMillan, Corey
Menon, Vilas
Wu, Lani
Altschuler, Steven
Lerner, Yossef
Sattler, Rita
Van Keuren-Jensen, Kendall
Rozenblatt-Rosen, Orit
Lindblad-Toh, Kerstin
Nicholson, Katharine
Gregersen, Peter
Lee, Jeong-Ho
Kokos, Sulev
Muljo, Stephen
Newcombe, Jia
Gustavsson, Emil K.
Seddighi, Sahba
Reyes, Joel F.
Coon, Steven L.
Ramos, Daniel
Schiavo, Giampietro
Fisher, Elizabeth M. C.
Secrier, Maria
Lashley, Tammaryn
Ule, Jernej
Buratti, Emanuele
Humphrey, Jack
Ward, Michael E.
Human Genetics
ARD - Amsterdam Reproduction and Development
Pathology
ANS - Cellular & Molecular Mechanisms
Source :
Nature, 603(7899), 131-137. Nature Publishing Group, Nature, vol 603, iss 7899, NYGC ALS Consortium 2022, ' TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A ', Nature, vol. 603, no. 7899, pp. 131-137 . https://doi.org/10.1038/s41586-022-04436-3, Nature, 603(7899), 131-+. NATURE PORTFOLIO
Publication Year :
2022
Publisher :
The Francis Crick Institute, 2022.

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.

Details

ISSN :
00280836
Database :
OpenAIRE
Journal :
Nature, 603(7899), 131-137. Nature Publishing Group, Nature, vol 603, iss 7899, NYGC ALS Consortium 2022, ' TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A ', Nature, vol. 603, no. 7899, pp. 131-137 . https://doi.org/10.1038/s41586-022-04436-3, Nature, 603(7899), 131-+. NATURE PORTFOLIO
Accession number :
edsair.doi.dedup.....94a25848cce9d1ba10e3d3a48fd3e242
Full Text :
https://doi.org/10.25418/crick.19345568