Ageing exacerbates ribosome pausing to disrupt cotranslational proteostasis

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.