UMMS Affiliation

Department of Neurology

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Cell Biology | Nervous System Diseases | Neurology


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.


ALS, C9ORF72, DPRs, FTD, U2 snRNP, iPSC-derived motor neurons, poly-GR, poly-PR, pre-mRNA splicing, toxic polydipeptide repeats

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Copyright © 2017 The Author(s).

DOI of Published Version



Cell Rep. 2017 Jun 13;19(11):2244-2256. doi: 10.1016/j.celrep.2017.05.056. Link to article on publisher's site

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Cell reports

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Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.