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Charcot-Marie-Tooth mutation in glycyl-tRNA synthetase stalls ribosomes in a pre-accommodation state and activates

Samantha Mendonsa1,2, Nicolai von Kuegelgen1,2, Lucija Bujanic1

  • 1Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.

Nucleic Acids Research
|August 17, 2021
PubMed

Insights

Toxic mutations in glycyl-tRNA synthetase (GARS) cause Charcot-Marie-Tooth disease by disrupting translation. These GARS mutations inhibit protein elongation and trigger stress responses, leading to neurodegeneration.

Area of Science:

  • Molecular Biology
  • Neuroscience
  • Genetics

Background:

  • Charcot-Marie-Tooth (CMT) disease is a peripheral neuropathy linked to toxic gain-of-function mutations in aminoacyl-tRNA synthetases.
  • These mutations impair translation, but the precise mechanism remains unclear despite normal aminoacylation activity.

Purpose of the Study:

  • To elucidate the mechanism by which CMT mutant glycyl-tRNA synthetase (CMT-GARS) disrupts translation.
  • To investigate the downstream effects of CMT-GARS on ribosome function and cellular stress responses.

Main Methods:

  • High-resolution ribosome profiling to analyze translation dynamics.
  • Reporter assays to assess translational control mechanisms.

Main Results:

  • CMT-GARS mutants reduce the availability of glycyl-tRNAGly for translation.
  • Mutants inhibit the elongation step by preventing glycyl-tRNA accommodation, causing ribosome pausing at glycine codons.
  • Ribosome pausing triggers integrated stress response via eIF2 phosphorylation, repressing translation initiation.

Conclusions:

  • CMT-GARS mutants induce translational repression through a dual mechanism affecting both elongation and initiation.
  • This detailed understanding of translational disruption offers potential therapeutic targets for CMT disease.

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