Deubiquitylating enzyme (DUB) (DUB)

Deubiquitylating enzymes (DUBs) are a large family of proteases that regulate the ubiquitin-proteasome system and autophagy by removing ubiquitin chains from substrate proteins. In the brain, specific DUBs such as UCH-L1, USP14, and USP30 are critical for maintaining protein homeostasis, synaptic function, and mitochondrial integrity. Dysregulation of these enzymes is strongly linked to neurodegenerative diseases, including Parkinson's and Alzheimer's, where the accumulation of misfolded proteins is a hallmark. For instance, UCH-L1 is highly abundant in neurons and is involved in ubiquitin recycling, while USP30 regulates mitophagy, the clearance of damaged mitochondria. Therapeutic strategies targeting brain-localized DUBs involve small-molecule inhibitors designed to restore proteostasis or enhance the degradation of toxic protein aggregates. However, achieving selectivity among the approximately 100 human DUBs and ensuring blood-brain barrier penetration remain significant challenges in drug development.

Other names

Deubiquitinating enzymeDeubiquitinaseUbiquitin-specific proteaseUbiquitin hydrolaseUbiquitin carboxyl-terminal hydrolase

Inhibition of the catalytic activity of deubiquitylating enzymes to prevent the removal of ubiquitin from substrate proteins, thereby promoting substrate degradation or modulating signaling pathways.