Xi Yu1  · Qinshuai Ni2  · Litong Han1  · Shenghan Zhang1  · Huamin Xu3  · Junxia Xie1  · Yingjuan Liu1

1 Institute of Brain Science and Disease, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Qingdao University, Qingdao 266071, China 

2 Qingdao Traditional Chinese Medicine Hospital, Qingdao Hiser Hospital Affiliated to Qingdao University, Qingdao 266033, China 

3 Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Brain Diseases and State Key Disciplines: Physiology, Department of Physiology, School of Basic Medicine, Qingdao University, Qingdao 266071, China

Abstract

Parkinson’s disease (PD), a neurodegenerative disorder, is significantly influenced by genetic predispositions, aging, and environmental factors. Central to PD pathology are mechanisms such as aberrant α-synuclein aggregation, mitochondrial dysfunction, oxidative stress, neuroinflammation, and ferroptosis, all of which are closely associated with dysregulated protein post-translational modifications. Ubiquitination, a critical reversible modification, acts as a pivotal bridge connecting the ubiquitin-proteasome system and the lysosomal-autophagy pathway, with its dynamics finely counterbalanced by deubiquitinating enzymes (DUBs). Notably, under pathological conditions, many DUBs exacerbate disease by stabilizing toxic α-syn aggregates and suppressing mitophagy. This review synthesizes current knowledge on how ubiquitin signaling orchestrates PD pathogenesis and highlights the emerging therapeutic potential of targeting specific DUBs with small molecule inhibitors to restore proteostasis and mitochondrial quality control, offering novel strategies for disease modification in PD.

Keywords

Parkinson disease; Deubiquitinating enzymes; Ubiquitination; Mitophagy; α-synuclein

[SpringerLink]