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Ribosome inhibition by C9ORF72-ALS/FTD-associated poly-PR and poly-GR proteins revealed by cryo-EM

Anna B Loveland1, Egor Svidritskiy1, Denis Susorov1

  • 1RNA Therapeutics Institute, UMass Chan Medical School, 368 Plantation Street, Worcester, MA, 01605, USA.

Nature Communications
|May 19, 2022
PubMed

Insights

Toxic dipeptide-repeat proteins from the C9ORF72 gene block ribosome function. These proteins, poly-PR and poly-GR, inhibit translation by physically obstructing the ribosomal tunnel, explaining their toxicity in neurodegenerative diseases.

Area of Science:

  • Molecular Biology
  • Neuroscience
  • Genetics

Background:

  • The C9ORF72 gene mutation is the leading genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
  • Toxic dipeptide-repeat (DPR) proteins, including poly-PR and poly-GR, are produced from these expanded G4C2 repeats.
  • The mechanism by which these DPR proteins repress cellular translation and cause toxicity is not fully understood.

Purpose of the Study:

  • To elucidate the molecular mechanism by which poly-PR and poly-GR inhibit cellular translation.
  • To determine the structural basis for the toxicity of these DPR proteins in C9ORF72-associated neurodegenerative diseases.

Main Methods:

  • Utilized cryogenic electron microscopy (cryo-EM) to visualize the interaction of DPR proteins with ribosomes.
  • Assessed the peptidyl-transferase activity of ribosomes in the presence of poly-PR and poly-GR.
  • Investigated the competitive binding between DPR proteins and the known ribosomal inhibitor erythromycin.

Main Results:

  • Poly-PR and poly-GR proteins, with at least 20 repeats, inhibit ribosome peptidyl-transferase activity at nanomolar concentrations.
  • Cryo-EM revealed that these DPR proteins bind within the ribosome's polypeptide tunnel, obstructing the peptidyl-transferase center (PTC).
  • Erythromycin binding in the tunnel competed with poly-PR, restoring peptidyl-transferase activity, indicating a shared binding site.

Conclusions:

  • Poly-PR and poly-GR exert toxicity by strongly and specifically binding within the ribosomal tunnel, thereby blocking translation.
  • This study reveals the structural mechanism underlying DPR protein toxicity in C9ORF72-ALS and FTD.
  • Understanding this mechanism offers potential therapeutic targets for these devastating neurodegenerative diseases.

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