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Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS

Ana Jovičić1, Jerome Mertens2, Steven Boeynaems3,4

  • 1Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.

Nature Neuroscience
|August 27, 2015
PubMed

Insights

Mutations in C9orf72 cause ALS and FTD. Researchers identified key cellular transport proteins that modify the toxic effects of dipeptide repeat proteins, offering new therapeutic targets for these neurodegenerative diseases.

Area of Science:

  • Neuroscience
  • Genetics
  • Molecular Biology

Background:

  • C9orf72 mutations are the leading genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
  • Toxic dipeptide repeat proteins (DPRs) arise from repeat expansions in C9orf72, driving neurodegeneration in various models.

Purpose of the Study:

  • To identify genetic modifiers of DPR toxicity.
  • To uncover potential therapeutic targets for C9orf72-associated neurodegenerative diseases.

Main Methods:

  • Conducted two unbiased genetic screens in Saccharomyces cerevisiae.
  • Utilized yeast models to identify genes that modulate DPR-induced toxicity.

Main Results:

  • Identified potent modifiers of DPR toxicity, including karyopherins.
  • Found that effectors of Ran-mediated nucleocytoplasmic transport significantly impact DPR toxicity.

Conclusions:

  • Nucleocytoplasmic transport pathways are critical in C9orf72-associated neurodegeneration.
  • Karyopherins and related transport mechanisms represent promising therapeutic targets for ALS and FTD.

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