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Oxidative stress causes a reversible decrease of deubiquitylases activity in old vertebrate brains - DUB

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. We identified a subset of DUBs that progressively lose catalytic activity with age, despite stable protein levels. We demonstrated that oxidative stress impairs DUB function through thiol oxidation and that antioxidant treatment by N-acetylcysteine ethyl ester (NACET) restores their activity in vitro and in vivo. Moreover, global DUB inhibition as well as targeted inhibition of USP7, one of the DUBs most strongly affected during aging, in human iPSC-derived neurons partially recapitulated ubiquitylation changes observed in aged brains. Temporal analysis in mice further 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: MSV000100403 | MassIVE | Thu Jan 08 02:08:00 GMT 2026

SECONDARY ACCESSION(S): PXD072807

REPOSITORIES: MassIVE

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