Evidence that C9ORF72 Dipeptide Repeat Proteins Associate with U2 snRNP to Cause Mis-splicing in ALS/FTD Patients
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 understoo...
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doaj-276e7a576bff44509730415cc6de8d742020-11-24T21:33:09ZengElsevierCell Reports2211-12472017-06-0119112244225610.1016/j.celrep.2017.05.056Evidence that C9ORF72 Dipeptide Repeat Proteins Associate with U2 snRNP to Cause Mis-splicing in ALS/FTD PatientsShanye Yin0Rodrigo Lopez-Gonzalez1Ryan C. Kunz2Jaya Gangopadhyay3Carl Borufka4Steven P. Gygi5Fen-Biao Gao6Robin Reed7Department of Cell Biology, Harvard Medical School, 240 Longwood Ave, Boston, MA 02115, USADepartment of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USADepartment of Cell Biology, Harvard Medical School, 240 Longwood Ave, Boston, MA 02115, USADepartment of Cell Biology, Harvard Medical School, 240 Longwood Ave, Boston, MA 02115, USADepartment of Cell Biology, Harvard Medical School, 240 Longwood Ave, Boston, MA 02115, USADepartment of Cell Biology, Harvard Medical School, 240 Longwood Ave, Boston, MA 02115, USADepartment of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USADepartment of Cell Biology, Harvard Medical School, 240 Longwood Ave, Boston, MA 02115, USAHexanucleotide 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 ∼44% of the mis-spliced cassette exons in C9ORF72 patient brains.http://www.sciencedirect.com/science/article/pii/S2211124717307131pre-mRNA splicingU2 snRNPALSFTDC9ORF72toxic polydipeptide repeatsDPRspoly-GRpoly-PRiPSC-derived motor neurons |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Shanye Yin Rodrigo Lopez-Gonzalez Ryan C. Kunz Jaya Gangopadhyay Carl Borufka Steven P. Gygi Fen-Biao Gao Robin Reed |
spellingShingle |
Shanye Yin Rodrigo Lopez-Gonzalez Ryan C. Kunz Jaya Gangopadhyay Carl Borufka Steven P. Gygi Fen-Biao Gao Robin Reed Evidence that C9ORF72 Dipeptide Repeat Proteins Associate with U2 snRNP to Cause Mis-splicing in ALS/FTD Patients Cell Reports pre-mRNA splicing U2 snRNP ALS FTD C9ORF72 toxic polydipeptide repeats DPRs poly-GR poly-PR iPSC-derived motor neurons |
author_facet |
Shanye Yin Rodrigo Lopez-Gonzalez Ryan C. Kunz Jaya Gangopadhyay Carl Borufka Steven P. Gygi Fen-Biao Gao Robin Reed |
author_sort |
Shanye Yin |
title |
Evidence that C9ORF72 Dipeptide Repeat Proteins Associate with U2 snRNP to Cause Mis-splicing in ALS/FTD Patients |
title_short |
Evidence that C9ORF72 Dipeptide Repeat Proteins Associate with U2 snRNP to Cause Mis-splicing in ALS/FTD Patients |
title_full |
Evidence that C9ORF72 Dipeptide Repeat Proteins Associate with U2 snRNP to Cause Mis-splicing in ALS/FTD Patients |
title_fullStr |
Evidence that C9ORF72 Dipeptide Repeat Proteins Associate with U2 snRNP to Cause Mis-splicing in ALS/FTD Patients |
title_full_unstemmed |
Evidence that C9ORF72 Dipeptide Repeat Proteins Associate with U2 snRNP to Cause Mis-splicing in ALS/FTD Patients |
title_sort |
evidence that c9orf72 dipeptide repeat proteins associate with u2 snrnp to cause mis-splicing in als/ftd patients |
publisher |
Elsevier |
series |
Cell Reports |
issn |
2211-1247 |
publishDate |
2017-06-01 |
description |
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 ∼44% of the mis-spliced cassette exons in C9ORF72 patient brains. |
topic |
pre-mRNA splicing U2 snRNP ALS FTD C9ORF72 toxic polydipeptide repeats DPRs poly-GR poly-PR iPSC-derived motor neurons |
url |
http://www.sciencedirect.com/science/article/pii/S2211124717307131 |
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