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

Alan S Premasiri,Anna L Gill,Fernando G Vieira

doi:10.3389/fphar.2020.569661

Abstract

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.

Highlights

A mutation in the C9orf72 gene is the most common known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (DeJesus-Hernandez et al, 2011; Renton et al, 2011)
Because multiple protein arginine methyltransferases (PRMT) are capable of catalyzing asymmetric dimethylation of arginine residues, multiple small molecule inhibitors were selected with varying potencies against the various type I PRMTs
We determined that polyGR is subject to asymmetric dimethylation (ADMe) modification, and the ADMe of exogenous polyGR and polyPR is crucial to the toxicity caused by the arginine-rich dipeptide repeats

Summary

Introduction

A mutation in the C9orf gene is the most common known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (DeJesus-Hernandez et al, 2011; Renton et al, 2011). The arginine-containing DRPs in particular have been demonstrated to have detrimental effects in several model systems and to interact with several different pathways

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Results

Conclusion