Journal
HUMAN MOLECULAR GENETICS
Volume 25, Issue 9, Pages 1803-1813Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddw052
Keywords
-
Funding
- National Institutes of Health/NIDDK [DK067493, DK020579]
- National Institutes of Health/NINDS [NS078398]
- Washington University Institute of Clinical and Translational Sciences from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health [UL1 TR000448]
- Japan Intractable Diseases Research Foundation
- Japan Society for the Promotion of Science
Ask authors/readers for more resources
The expansion of the GGGGCC hexanucleotide repeat in the non-coding region of the Chromosome 9 open-reading frame 72 (C9orf72) gene is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). This genetic alteration leads to the accumulation of five types of poly-dipeptides translated from the GGGGCC hexanucleotide repeat. Among these, poly-proline-arginine (poly-PR) and poly-glycine-arginine (poly-GR) peptides are known to be neurotoxic. However, the mechanisms of neurotoxicity associated with these poly-dipeptides are not clear. A proteomics approach identified a number of interacting proteins with poly-PR peptide, including mRNA-binding proteins, ribosomal proteins, translation initiation factors and translation elongation factors. Immunostaining of brain sections from patients with C9orf72 ALS showed that poly-GR was colocalized with a mRNA-binding protein, hnRNPA1. In vitro translation assays showed that poly-PR and poly-GR peptides made insoluble complexes with mRNA, restrained the access of translation factors to mRNA, and blocked protein translation. Our results demonstrate that impaired protein translation mediated by poly-PR and poly-GR peptides plays a role in neurotoxicity and reveal that the pathways altered by the poly-dipeptides-mRNA complexes are potential therapeutic targets for treatment of C9orf72 FTD/ALS.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available