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Oxidative stress decreases deubiquitylases and proteasome activity during vertebrate brain aging

ABSTRACT: The ubiquitin-proteasome system (UPS) is essential for maintaining neuronal proteostasis. However, how deubiquitylating enzymes (DUBs), key regulators of substrate stability and signaling, functionally change during brain aging in vertebrates remains poorly understood. We systematically profiled active cysteine DUBs using activity based proteomics in aging mouse 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 longitudinal 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): Nothobranchius Furzeri (ncbitaxon:105023)

SUBMITTER: Alessandro Ori

PROVIDER: MSV000098114 | MassIVE | Wed Jun 11 00:34:00 BST 2025

SECONDARY ACCESSION(S): PXD064860

REPOSITORIES: MassIVE

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