Deubiquitinating enzymes in parkinson’s disease: molecular mechanisms and therapeutic potential

TL;DR

This paper reviews how deubiquitinating enzymes (DUBs) contribute to Parkinson’s disease and their potential as therapeutic targets.

Contribution

The paper provides a comprehensive overview of DUBs' roles in PD pathogenesis and highlights recent advances in DUB-targeted therapies.

Findings

DUBs are linked to PD through their regulation of α-synuclein aggregation and mitochondrial stress.

Modulating DUBs can reduce PD-related pathologies and improve neuronal survival.

DUB inhibitors offer multi-pathway therapeutic potential for PD.

Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the pathological accumulation of α-synuclein aggregates and the selective degeneration of dopaminergic neurons in the substantia nigra. Growing evidence implicates dysfunction of the ubiquitin-proteasome system (UPS), a critical regulator of protein homeostasis, in the pathogenesis of PD through impaired clearance of toxic protein species. As key components of the UPS, deubiquitinating enzymes (DUBs) counterbalance ubiquitin ligase activity by cleaving ubiquitin chains from substrate proteins, thereby playing pivotal roles in maintaining protein turnover and regulating cellular signaling pathways. Notably, emerging research has demonstrated that specific DUBs are intimately involved in modulating multiple PD-related pathological processes, including α-synuclein aggregation, mitochondrial oxidative stress, iron homeostasis, and neuronal survival. These findings suggest DUBs as promising therapeutic targets for PD intervention. This review comprehensively summarize the pathophysiological roles of PD-associated DUBs, their molecular mechanisms in disease progression, and recent advances in the development of DUB inhibitors as potential disease-modifying therapies for PD.

DUB dysfunction is mechanistically linked to PD pathogenesis.

DUBs integrate proteostasis imbalance and neurodegeneration by regulating α-synuclein dynamics, mitochondrial integrity, and neuronal survival.

Specific DUB modulators significantly ameliorate PD-related pathologies.

DUB-targeted strategies offer superior multi-pathway intervention compared to conventional single-target therapies for PD.

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