The Role of Copper and Solid Lipid Nanoparticles in Parkinson’s Disease Pathogenesis and Therapy

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The disease hallmark is Lewy bodies (LBs) in surviving neurons, primarily composed of α-synuclein protein. In PD, α-synuclein is often phosphorylated at Serine 129 (pS129), promoting its aggregation and interaction with metal ions like copper, which accelerates α-synuclein aggregation into fibrillar plaques. This study explored copper's role in PD pathogenesis, focusing on α-synuclein clearance via autophagy and ubiquitin-proteasome system (UPS). A human neuronal model, SH-SY5Y cells, was developed, demonstrating dopaminergic characteristics suitable for PD studies. Copper overload was induced using copper chloride, which increased autophagy markers and altered the PI3K/AKT/mTOR pathway, promoting autophagy but impairing autophagic flux and UPS, leading to increased α-synuclein levels. The study also examined copper overload in cells overexpressing α-synuclein, revealing that copper exposure increased cytotoxicity and lysosomal activity, further impairing protein degradation mechanisms. Additionally, solid lipid nanoparticles (SLNs) containing grape seed extract (GSE) and dopamine (DA) were tested, showing cytoprotective effects against rotenone-induced toxicity, oxidative stress, and increased α-synuclein levels. SLNs show therapeutic potential for noninvasive approach to PD, supporting the hypothesis that copper dyshomeostasis compromises α-synuclein clearance, exacerbating cellular dysfunction and stress.