Oxidative Stress Impairs Deubiquitylase Activity in the Aging Brain
Some evidence suggests that deubiquitylases are relevant to aging. These enzymes remove ubiquitin from proteins; recall that the decoration of a protein with ubiquitin enables it to be broken down into raw materials for further protein synthesis by a proteasome. Alongside autophagy, the ubiquitin-proteasome system is one of the important processes by which a cell maintains quality control and otherwise manages its contents. Managing which proteins are flagged by ubiquitin necessarily involves removal, not just addition, and thus the existence of deubiquitylases. Here, researchers provide evidence for rising levels of oxidative stress in the aging brain to impair the activity of deubiquitylases. As is usually the case in these matters, it is unknown as to the relative importance of this issue versus all of the other problems produced by age-related change in the operation of cellular biochemistry.
Among the cellular mechanisms governing proteostasis, the ubiquitin-proteasome system (UPS) plays a central role in signaling, stress responses, and protein degradation by attaching ubiquitin to lysine residues of specific target proteins. Within the UPS, ubiquitin ligases and deubiquitylases (DUBs) act antagonistically to modulate protein fate and signaling pathways dynamically. Altering DUB activity has been linked to lifespan in nematodes, and dysregulation of specific DUBs in humans leads to several neurodegenerative diseases, such as spinocerebellar ataxia and Parkinson's disease. However, a systematic understanding of how DUB functions is altered in the aging brain, the mechanisms driving these changes, and the consequences of altered DUB activity at the molecular level are still lacking.
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 induced pluripotent stem cell-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.