Type I PRMT Inhibition Protects Against C9ORF72 Arginine-Rich Dipeptide Repeat Toxicity

Type I PRMT Inhibition Protects Against C9ORF72 Arginine-Rich Dipeptide Repeat Toxicity

Repeat expansion mutations in the C9ORF72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Repeat-associated non-AUG translation of this expansion produces dipeptide repeat proteins (DRPs). The arginine containing DRPs, polyGR and polyP...

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Bibliographic Details
Main Authors: Alan S. Premasiri, Anna L. Gill, Fernando G. Vieira
Format: Article
Language:English
Published: Frontiers Media S.A. 2020-09-01
Series:Frontiers in Pharmacology
Subjects:
ALS (Amyotrophic lateral sclerosis)
FTD (Fronto-Temporal Dementia)
C9ORF72 DPRs
arginine methylation
protein arginine methyl transferase
glycine-arginine
Online Access:https://www.frontiersin.org/article/10.3389/fphar.2020.569661/full
Description
Summary:Repeat expansion mutations in the C9ORF72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Repeat-associated non-AUG translation of this expansion produces dipeptide repeat proteins (DRPs). The arginine containing DRPs, polyGR and polyPR, are consistently reported to be the most toxic. Here we demonstrated that small molecule inhibition of type I protein arginine methyltransferases (PRMT) protects against polyGR and polyPR toxicity. Furthermore, our findings suggest that asymmetric dimethylation of polyGR and polyPR by Type I PRMTs plays important roles in their cytotoxicity.
ISSN:1663-9812

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