Oxidative Stress Impairs Deubiquitylase Activity in the Aging Brain

Key Takeaways

• Oxidative stress oxidizes DUB thiols, reducing activity in aged brains
• Activity-based proteomics identified DUBs that lose function despite stable levels
• NACET antioxidant restores DUB activity, suggesting reversible proteostasis impairment
• DUB inhibition appears before proteasome decline, indicating early aging marker

Pulse Analysis

The ubiquitin‑proteasome system (UPS) is the cell’s primary mechanism for tagging and recycling proteins, and its balance hinges on both ubiquitin ligases and deubiquitylases (DUBs). While the addition of ubiquitin flags proteins for degradation, DUBs remove these tags, fine‑tuning proteostasis and signaling pathways. Age‑related oxidative stress has long been implicated in neurodegeneration, yet its direct impact on DUB enzymatic function remained unclear. Understanding how redox changes alter DUB activity is essential for mapping the cascade that leads from molecular damage to cognitive decline.

In a cross‑species proteomic survey, the authors applied activity‑based profiling to mouse and killifish brains, uncovering a cohort of cysteine‑dependent DUBs whose catalytic output wanes with age despite constant expression levels. The decline correlated with thiol oxidation, a reversible modification induced by accumulated reactive oxygen species. Treatment with the cell‑permeable antioxidant N‑acetylcysteine ethyl ester (NACET) re‑activated these enzymes, confirming oxidative inhibition as the primary mechanism. Targeted knock‑down of USP7, the most affected DUB, reproduced the ubiquitylation shifts observed in aged neuronal cultures.

These findings reposition redox‑sensitive DUBs as early biomarkers and actionable nodes in brain aging. Because DUB inhibition precedes measurable proteasome loss, therapeutic strategies that restore DUB function—whether through antioxidants like NACET or small‑molecule DUB activators—could halt or reverse proteostasis collapse before irreversible damage accrues. The study also highlights the value of activity‑based proteomics for drug discovery, offering a template to screen compounds that protect DUB thiols. Future work will need to translate these preclinical insights into human trials aimed at preserving cognitive health.