TDP-43 represses cryptic exon inclusion in the FTD–ALS gene UNC13A

X. Rosa Ma, Mercedes Prudencio, Yuka Koike, Sarat C. Vatsavayai, Garam Kim, Fred Harbinski, Adam Briner, Caitlin M. Rodriguez, Caiwei Guo, Tetsuya Akiyama, H. Broder Schmidt, Beryl B. Cummings, David W. Wyatt, Katherine Kurylo, Georgiana Miller, Shila Mekhoubad, Nathan Sallee, Gemechu Mekonnen, Laura Ganser, Jack D. Rubien, Karen Jansen-West, Casey N. Cook, Sarah Pickles, Björn Oskarsson, Neill R. Graff-Radford, Bradley F. Boeve, David S. Knopman, Ronald C. Petersen, Dennis W. Dickson, James Shorter, Sua Myong, Eric M. Green, William W. Seeley, Leonard Petrucelli () and Aaron D. Gitler ()
Additional contact information
X. Rosa Ma: Stanford University School of Medicine
Mercedes Prudencio: Mayo Clinic
Yuka Koike: Mayo Clinic
Sarat C. Vatsavayai: University of California San Francisco
Garam Kim: Stanford University School of Medicine
Fred Harbinski: Maze Therapeutics
Adam Briner: Stanford University School of Medicine
Caitlin M. Rodriguez: Stanford University School of Medicine
Caiwei Guo: Stanford University School of Medicine
Tetsuya Akiyama: Stanford University School of Medicine
H. Broder Schmidt: Stanford University School of Medicine
Beryl B. Cummings: Maze Therapeutics
David W. Wyatt: Maze Therapeutics
Katherine Kurylo: Maze Therapeutics
Georgiana Miller: Maze Therapeutics
Shila Mekhoubad: Maze Therapeutics
Nathan Sallee: Maze Therapeutics
Gemechu Mekonnen: Johns Hopkins University
Laura Ganser: Johns Hopkins University
Jack D. Rubien: University of Pennsylvania
Karen Jansen-West: Mayo Clinic
Casey N. Cook: Mayo Clinic
Sarah Pickles: Mayo Clinic
Björn Oskarsson: Mayo Clinic
Neill R. Graff-Radford: Mayo Clinic
Bradley F. Boeve: Mayo Clinic
David S. Knopman: Mayo Clinic
Ronald C. Petersen: Mayo Clinic
Dennis W. Dickson: Mayo Clinic
James Shorter: University of Pennsylvania
Sua Myong: Johns Hopkins University
Eric M. Green: Maze Therapeutics
William W. Seeley: University of California San Francisco
Leonard Petrucelli: Mayo Clinic
Aaron D. Gitler: Stanford University School of Medicine

Nature, 2022, vol. 603, issue 7899, 124-130

Abstract: Abstract A hallmark pathological feature of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the depletion of RNA-binding protein TDP-43 from the nucleus of neurons in the brain and spinal cord1. A major function of TDP-43 is as a repressor of cryptic exon inclusion during RNA splicing2–4. Single nucleotide polymorphisms in UNC13A are among the strongest hits associated with FTD and ALS in human genome-wide association studies5,6, but how those variants increase risk for disease is unknown. Here we show that TDP-43 represses a cryptic exon-splicing event in UNC13A. Loss of TDP-43 from the nucleus in human brain, neuronal cell lines and motor neurons derived from induced pluripotent stem cells resulted in the inclusion of a cryptic exon in UNC13A mRNA and reduced UNC13A protein expression. The top variants associated with FTD or ALS risk in humans are located in the intron harbouring the cryptic exon, and we show that they increase UNC13A cryptic exon splicing in the face of TDP-43 dysfunction. Together, our data provide a direct functional link between one of the strongest genetic risk factors for FTD and ALS (UNC13A genetic variants), and loss of TDP-43 function.

Date: 2022
References: Add references at CitEc
Citations: View citations in EconPapers (8)

Downloads: (external link)
https://www.nature.com/articles/s41586-022-04424-7 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:603:y:2022:i:7899:d:10.1038_s41586-022-04424-7

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-022-04424-7

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().