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Oxidative stress decreases deubiquitylases and proteasome activity during vertebrate brain aging - PRM Analysis

ABSTRACT: The ubiquitin-proteasome system is essential for neuronal proteostasis and its activity declines with age. How deubiquitylating enzymes (DUBs) are affected by aging in the vertebrate brain remains unclear. Here, we profiled cysteine protease DUBs using activity-based proteomics in aging mice and killifish brains. Despite stable protein levels, we identified a subset of DUBs that progressively lose catalytic activity with age. We demonstrated that oxidative stress impairs DUB function through thiol oxidation and that antioxidant treatment restores their activity in vitro and in vivo. Further, inhibition of DUBs in human iPSC-derived neurons significantly recapitulated ubiquitylation changes observed in aged brains, and temporal analysis in mice revealed that DUB inhibition precedes proteasome decline in the brain during aging. Together, these findings indicate a redox-sensitive subset of DUBs that undergo an age-associated decline in activity and suggest that impaired deubiquitylation is an early, yet potentially reversible, driver of proteostasis decline in the aging brain.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Alessandro Ori

PROVIDER: MSV000098802 | MassIVE | Tue Aug 12 00:22:00 BST 2025

SECONDARY ACCESSION(S): PXD067249

REPOSITORIES: MassIVE

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Oxidative stress decreases deubiquitylases and proteasome activity during vertebrate brain aging

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Oxidative stress decreases deubiquitylases and proteasome activity during vertebrate brain aging

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