UMMS Affiliation
Department of Neurology
Publication Date
2017-06-13
Document Type
Article
Disciplines
Cell Biology | Nervous System Diseases | Neurology
Abstract
Hexanucleotide repeat expansion in the C9ORF72 gene results in production of dipeptide repeat (DPR) proteins that may disrupt pre-mRNA splicing in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients. At present, the mechanisms underlying this mis-splicing are not understood. Here, we show that addition of proline-arginine (PR) and glycine-arginine (GR) toxic DPR peptides to nuclear extracts blocks spliceosome assembly and splicing, but not other types of RNA processing. Proteomic and biochemical analyses identified the U2 small nuclear ribonucleoprotein particle (snRNP) as a major interactor of PR and GR peptides. In addition, U2 snRNP, but not other splicing factors, mislocalizes from the nucleus to the cytoplasm both in C9ORF72 patient induced pluripotent stem cell (iPSC)-derived motor neurons and in HeLa cells treated with the toxic peptides. Bioinformatic studies support a specific role for U2-snRNP-dependent mis-splicing in C9ORF72 patient brains. Together, our data indicate that DPR-mediated dysfunction of U2 snRNP could account for as much as approximately 44% of the mis-spliced cassette exons in C9ORF72 patient brains.
Keywords
ALS, C9ORF72, DPRs, FTD, U2 snRNP, iPSC-derived motor neurons, poly-GR, poly-PR, pre-mRNA splicing, toxic polydipeptide repeats
Rights and Permissions
Copyright © 2017 The Author(s).
DOI of Published Version
10.1016/j.celrep.2017.05.056
Source
Cell Rep. 2017 Jun 13;19(11):2244-2256. doi: 10.1016/j.celrep.2017.05.056. Link to article on publisher's site
Journal/Book/Conference Title
Cell reports
Related Resources
PubMed ID
28614712
Repository Citation
Yin, Shanye; Lopez-Gonzalez, Rodrigo; Kunz, Ryan C.; Gangopadhyay, Jaya; Borufka, Carl; Gygi, Steven P.; Gao, Fen-Biao; and Reed, Robin, "Evidence that C9ORF72 Dipeptide Repeat Proteins Associate with U2 snRNP to Cause Mis-splicing in ALS/FTD Patients" (2017). Open Access Articles. 3181.
https://escholarship.umassmed.edu/oapubs/3181
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.