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Updated: Dec 6, 2025

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

Alan S Premasiri1, Anna L Gill1, Fernando G Vieira1

  • 1ALS Therapy Development Institute, Cambridge, MA, United States.

Frontiers in Pharmacology
|October 5, 2020
PubMed

Insights

Small molecules targeting protein arginine methyltransferases (PRMTs) reduce toxicity from C9ORF72 repeat expansions, a key cause of ALS and FTD. This suggests PRMT inhibition is a potential therapeutic strategy for these neurodegenerative diseases.

Area of Science:

  • Neuroscience
  • Genetics
  • Molecular Biology

Background:

  • C9ORF72 repeat expansions are the leading genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
  • These expansions produce toxic dipeptide repeat proteins (DRPs), with arginine-containing polyGR and polyPR being particularly harmful.

Purpose of the Study:

  • To investigate the role of protein arginine methyltransferases (PRMTs) in the toxicity of polyGR and polyPR.
  • To evaluate the therapeutic potential of inhibiting Type I PRMTs against C9ORF72-associated neurotoxicity.

Main Methods:

  • Utilized cell models expressing polyGR and polyPR to assess toxicity.
  • Administered small molecule inhibitors targeting Type I PRMTs.
  • Analyzed the impact of PRMT inhibition on DRP cytotoxicity and methylation status.

Main Results:

  • Small molecule inhibition of Type I PRMTs significantly protected against polyGR and polyPR toxicity.
  • Evidence suggests that asymmetric dimethylation of polyGR and polyPR by Type I PRMTs is crucial for their cytotoxic effects.

Conclusions:

  • Type I PRMTs and their methylation activity are key contributors to the toxicity of C9ORF72-associated DRPs.
  • Inhibiting Type I PRMTs represents a promising therapeutic avenue for treating ALS and FTD caused by C9ORF72 repeat expansions.
Keywords:
ALS (Amyotrophic lateral sclerosis)C9ORF72 DPRsFTD (Fronto-Temporal Dementia)arginine methylationglycine-arginineproline-arginineprotein arginine methyl transferase

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