Oxidative stress causes a reversible decrease of deubiquitylases activity in old vertebrate brains.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 42014687.
- Also identified by DOI 10.1038/s41467-026-71921-y and PMC identifier 13100221.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
The ubiquitin-proteasome system is essential for neuronal proteostasis, yet its function declines with age. How aging affects deubiquitylating enzymes (DUBs) in the vertebrate brain remains unclear. Here we used activity-based proteomics to profile cysteine protease DUBs in aging mouse and killifish brains. We identified a subset of DUBs that progressively lose catalytic activity with age despite stable protein abundance. Mechanistically, oxidative stress impaired DUB function through thiol oxidation, whereas antioxidant treatment with N-acetylcysteine ethyl ester (NACET) restored activity in aging brains. In human iPSC-derived neurons, global DUB inhibition and targeted inhibition of USP7, one of the most strongly age-affected DUBs, partially recapitulated ubiquitylation changes observed in aged brains. Temporal analysis in mice further revealed that DUB inhibition precedes proteasome decline during brain aging. Together, these findings identify redox-sensitive DUBs that lose activity with age and suggest impaired deubiquitylation as an early, potentially reversible driver of proteostasis decline in the aging brain.
Medical subject headings
- Oxidative Stress
- Brain
- Aging
- Deubiquitinating Enzymes