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Measuring RAN Peptide Toxicity in C. elegans
10:49

Measuring RAN Peptide Toxicity in C. elegans

Published on: April 30, 2020

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SRSF protein kinase 1 modulates RAN translation and suppresses CGG repeat toxicity

Indranil Malik1, Yi-Ju Tseng1,2, Shannon E Wright1,3

  • 1Department of Neurology, University of Michigan, Ann Arbor, MI, USA.

EMBO Molecular Medicine
|September 20, 2021
PubMed

Insights

Researchers found that serine/arginine-rich (SR) proteins bind to toxic CGG repeat RNAs, driving neurodegeneration in Fragile X-associated tremor/ataxia syndrome (FXTAS). Inhibiting serine/arginine protein kinases (SRPKs) reduced this toxicity.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • CGG repeat expansions in Fragile X-associated tremor/ataxia syndrome (FXTAS) lead to neurodegeneration.
  • These repeat RNAs sequester RNA-binding proteins (RBPs) and undergo toxic repeat-associated non-AUG (RAN) translation.

Purpose of the Study:

  • To identify RBPs involved in CGG repeat RNA processes.
  • To investigate the role of serine/arginine protein kinases (SRPKs) in RAN translation and repeat toxicity.

Main Methods:

  • Utilized a CGG repeat RNA-tagging system and mass spectrometry to identify interacting RBPs in mammalian cells.
  • Tested the effects of SRPK inhibition on RAN translation and toxicity in Drosophila and rodent neuron models.

Main Results:

  • Identified SR proteins that selectively interact with CGG repeat RNA.
  • Demonstrated that SRPK inhibition reduces RAN translation of CGG and GGGGCC repeats.
  • Showed that SRPK inhibition suppresses toxicity in FXTAS and C9orf72 ALS/FTD models.

Conclusions:

  • SR proteins play a role in CGG repeat RNA binding and toxicity.
  • SRPK inhibitors show therapeutic potential for repeat expansion disorders by modulating RAN translation.
Keywords:
C9orf72 ALSCGG repeatsFXTASRAN translationSRSF

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