Decode the Ubiquitinome in Parkinson's Disease: From Pathological Aggregates to Targeted DUB Therapeutics

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.