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

Area of Science:

• Neuroscience
• Biochemistry
• Aging Research

Background:

• The ubiquitin-proteasome system maintains neuronal proteostasis but declines with age.
• The impact of aging on deubiquitylating enzymes (DUBs) in the vertebrate brain is not well understood.

Purpose of the Study:

• To investigate how aging affects the activity of deubiquitylating enzymes (DUBs) in the brain.
• To identify specific DUBs affected by aging and the underlying mechanisms.

Main Methods:

• Activity-based proteomics was employed to profile cysteine protease DUBs in aging mouse and killifish brains.
• Oxidative stress and antioxidant treatments (NACET) were used to assess DUB function.
• Experiments in human iPSC-derived neurons and temporal analysis in mice were conducted.

Main Results:

• A subset of DUBs showed decreased catalytic activity with age, independent of protein abundance.
• Oxidative stress impaired DUB function via thiol oxidation; NACET restored activity in aged brains.
• DUB inhibition preceded proteasome decline in aging mouse brains, and partially mimicked age-related ubiquitylation changes.

Conclusions:

• Redox-sensitive DUBs lose activity during brain aging.
• Impaired deubiquitylation is an early, potentially reversible driver of proteostasis decline in the aging brain.