This review synthesizes in vitro, animal, and clinical evidence that copper dyshomeostasis promotes α-synuclein misfolding and impairs ubiquitin–proteasome and autophagy–lysosome clearance pathways, proposing selective modulation of intracellular copper pools as a potential therapeutic strategy for…

By connecting a modifiable metal imbalance to core PD mechanisms (α-synuclein proteostasis, oxidative stress, mitochondrial and lysosomal dysfunction) and outlining translational approaches to target intracellular copper, the paper identifies a plausibly actionable target and biomarker direction…

Parkinson's disease (PD) is characterized by the progressive degeneration of dopaminergic neurons and the accumulation of α-synuclein-rich inclusions, largely resulting from impaired protein clearance mechanisms. Copper is an essential redox-active metal in the central nervous system (CNS), but alterations in its homeostasis can promote oxidative stress, mitochondrial dysfunction, and proteostatic failure. In vitro studies indicate that copper can promote α-synuclein misfolding, enhance oxidative stress, and interfere with both the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway (ALP). In this review, we critically evaluate mechanistic evidence from cellular models, integrating available animal and clinical data to assess the biological significance of copper-mediated impairment of α-synuclein clearance. We highlight the current research, identify methodological limitations, and discuss whether copper imbalance acts as a primary pathogenic trigger or as a disease-modifying amplifier of proteostatic failure. Furthermore, we consider the translational implications of selectively modulating intracellular copper pools as a therapeutic strategy in PD. Finally, we will highlight unresolved issues, methodological limitations, and emerging targeted therapeutic prospects.