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Yeast screen for modifiers of C9orf72 poly(glycine-arginine) dipeptide repeat toxicity

Noori Chai1,2, Aaron D Gitler1

  • 1Department of Genetics, Stanford University School of Medicine, 300 Pasteur Drive, M322 Alway Building, Stanford, CA 94305, USA.

FEMS Yeast Research
|March 13, 2018
PubMed

Insights

The C9orf72 gene expansion causes ALS/FTD. Arginine-rich dipeptide repeat proteins (DPRs) like PR and GR are toxic. Their distinct genetic modifiers suggest different toxicity pathways.

Area of Science:

  • Neuroscience
  • Genetics
  • Molecular Biology

Background:

  • Hexanucleotide repeat expansions in C9orf72 are the leading genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
  • These expansions produce toxic dipeptide repeat (DPR) proteins, including proline-arginine (PR) and glycine-arginine (GR), which are implicated in neurodegeneration.

Purpose of the Study:

  • To investigate the toxicity mechanisms of GR proteins by comparing them to PR proteins.
  • To identify genetic modifiers of GR toxicity in yeast and compare them with previously identified modifiers of PR toxicity.

Main Methods:

  • Conducted a genetic screen in Saccharomyces cerevisiae to identify genes that modify proline-arginine (PR) and glycine-arginine (GR) toxicity.
  • Compared the identified genetic modifiers from the GR screen with those from a previous PR screen.

Main Results:

  • Identified numerous genetic modifiers for both PR and GR toxicity, many involved in nucleocytoplasmic transport.
  • Found a surprisingly small overlap between the genetic modifiers of PR and GR toxicity.

Conclusions:

  • The distinct sets of genetic modifiers suggest that PR and GR proteins may exert their toxicity through different molecular mechanisms.
  • Further research into these distinct pathways could reveal novel therapeutic targets for C9orf72-related ALS and FTD.

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