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Isolation of Ribosome Bound Nascent Polypeptides in vitro to Identify Translational Pause Sites Along mRNA
10:15

Isolation of Ribosome Bound Nascent Polypeptides in vitro to Identify Translational Pause Sites Along mRNA

Published on: July 6, 2012

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Ageing exacerbates ribosome pausing to disrupt cotranslational proteostasis

Kevin C Stein1, Fabián Morales-Polanco1, Joris van der Lienden1

  • 1Department of Biology, Stanford University, Stanford, CA, USA.

Nature
|January 20, 2022
PubMed

Insights

Ageing impairs cellular protein quality control by increasing ribosome pausing during translation. This leads to the accumulation of misfolded proteins and contributes to age-related decline.

Area of Science:

  • Molecular Biology
  • Gerontology
  • Cellular Biology

Background:

  • Cellular proteostasis declines with age, contributing to protein misfolding diseases.
  • The mechanisms by which ageing impairs proteostasis are not fully understood.
  • Nascent polypeptides pose a significant challenge to the proteostasis network.

Purpose of the Study:

  • To investigate the hypothesis that altered translational efficiency during ageing contributes to proteostasis collapse.
  • To elucidate the role of ribosome pausing and ribosome-associated quality control (RQC) in the ageing process.

Main Methods:

  • Comparative analysis of translation elongation kinetics in aged Caenorhabditis elegans and Saccharomyces cerevisiae.
  • Identification of ribosome pausing sites, including polybasic stretches.
  • Assessment of RQC substrate clearance and aggregation in aged yeast.
  • Correlation of lifespan with ribosome pausing and RQC pathway flux in yeast mutants.

Main Results:

  • Ageing alters translation elongation kinetics, exacerbating ribosome pausing at specific sites in yeast and worms.
  • Increased ribosome pausing leads to ribosome collisions and triggers the RQC pathway.
  • Aged yeast cells show impaired RQC substrate clearance and increased aggregation.
  • Long-lived yeast mutants exhibit reduced age-dependent ribosome pausing and enhanced RQC flux.
  • Nascent polypeptides with age-dependent ribosome pausing are enriched in age-dependent protein aggregates in C. elegans.

Conclusions:

  • Increased ribosome pausing during ageing overwhelms the RQC pathway, leading to nascent polypeptide aggregation.
  • This RQC overload critically contributes to proteostasis impairment and systemic decline during ageing.
  • Targeting translation efficiency and RQC could be potential strategies for mitigating age-related proteostasis decline.

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