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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Autores principales: Premasiri, Alan S., Gill, Anna L., Vieira, Fernando G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Pharmacology
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508178/
https://www.ncbi.nlm.nih.gov/pubmed/33013410
http://dx.doi.org/10.3389/fphar.2020.569661
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author Premasiri, Alan S.
Gill, Anna L.
Vieira, Fernando G.
author_facet Premasiri, Alan S.
Gill, Anna L.
Vieira, Fernando G.
author_sort Premasiri, Alan S.
collection PubMed
description 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.
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spelling pubmed-75081782020-10-02 Type I PRMT Inhibition Protects Against C9ORF72 Arginine-Rich Dipeptide Repeat Toxicity Premasiri, Alan S. Gill, Anna L. Vieira, Fernando G. Front Pharmacol Pharmacology 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. Frontiers Media S.A. 2020-09-08 /pmc/articles/PMC7508178/ /pubmed/33013410 http://dx.doi.org/10.3389/fphar.2020.569661 Text en Copyright © 2020 Premasiri, Gill and Vieira http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Premasiri, Alan S.
Gill, Anna L.
Vieira, Fernando G.
Type I PRMT Inhibition Protects Against C9ORF72 Arginine-Rich Dipeptide Repeat Toxicity
title Type I PRMT Inhibition Protects Against C9ORF72 Arginine-Rich Dipeptide Repeat Toxicity
title_full Type I PRMT Inhibition Protects Against C9ORF72 Arginine-Rich Dipeptide Repeat Toxicity
title_fullStr Type I PRMT Inhibition Protects Against C9ORF72 Arginine-Rich Dipeptide Repeat Toxicity
title_full_unstemmed Type I PRMT Inhibition Protects Against C9ORF72 Arginine-Rich Dipeptide Repeat Toxicity
title_short Type I PRMT Inhibition Protects Against C9ORF72 Arginine-Rich Dipeptide Repeat Toxicity
title_sort type i prmt inhibition protects against c9orf72 arginine-rich dipeptide repeat toxicity
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508178/
https://www.ncbi.nlm.nih.gov/pubmed/33013410
http://dx.doi.org/10.3389/fphar.2020.569661
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