Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta and the formation of Lewy bodies, abnormal protein aggregates primarily composed of α-synuclein. Copper, an essential trace element, plays a role in α-synuclein aggregation and PD pathogenesis. This study examines the effects of copper overload on α-synuclein clearance pathways, focusing on autophagy and the ubiquitin-proteasome system (UPS) in dopaminergic SH-SY5Y neuroblastoma cells. Copper exposure enhances autophagosome formation, as indicated by increased Beclin-1 and LC3-II levels, and impairs autophagic flux, evidenced by LC3-II accumulation in the presence of chloroquine. Concurrently, copper increases polyubiquitinated proteins, suggesting UPS dysfunction, which is confirmed through MG132 treatment. These disruptions lead to the accumulation and aggregation of α-synuclein, particularly in its phosphorylated form. Immunofluorescence reveals neurite-localized α-synuclein aggregates, consistent with copper's role in α-synuclein pathology. This study highlights copper dyshomeostasis as a contributor to impaired α-synuclein clearance through autophagy and UPS dysfunction, advancing the understanding of PD's molecular basis.
Copper Overload Affects α-Synuclein Clearance Mechanisms in a Parkinson's Disease In Vitro Model
Damato M.;Coppola C.;Greco M.;Maffia M.
2026-01-01
Abstract
Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta and the formation of Lewy bodies, abnormal protein aggregates primarily composed of α-synuclein. Copper, an essential trace element, plays a role in α-synuclein aggregation and PD pathogenesis. This study examines the effects of copper overload on α-synuclein clearance pathways, focusing on autophagy and the ubiquitin-proteasome system (UPS) in dopaminergic SH-SY5Y neuroblastoma cells. Copper exposure enhances autophagosome formation, as indicated by increased Beclin-1 and LC3-II levels, and impairs autophagic flux, evidenced by LC3-II accumulation in the presence of chloroquine. Concurrently, copper increases polyubiquitinated proteins, suggesting UPS dysfunction, which is confirmed through MG132 treatment. These disruptions lead to the accumulation and aggregation of α-synuclein, particularly in its phosphorylated form. Immunofluorescence reveals neurite-localized α-synuclein aggregates, consistent with copper's role in α-synuclein pathology. This study highlights copper dyshomeostasis as a contributor to impaired α-synuclein clearance through autophagy and UPS dysfunction, advancing the understanding of PD's molecular basis.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
