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Copper, an essential trace element, plays a role in \u03b1\u2010synuclein aggregation and PD pathogenesis. This study examines the effects of copper overload on \u03b1\u2010synuclein clearance pathways, focusing on autophagy and the ubiquitin\u2010proteasome system (UPS) in dopaminergic SH\u2010SY5Y neuroblastoma cells. Copper exposure enhances autophagosome formation, as indicated by increased Beclin\u20101 and LC3\u2010II levels, and impairs autophagic flux, evidenced by LC3\u2010II 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 \u03b1\u2010synuclein, particularly in its phosphorylated form. Immunofluorescence reveals neurite\u2010localized \u03b1\u2010synuclein aggregates, consistent with copper's role in \u03b1\u2010synuclein pathology. This study highlights copper dyshomeostasis as a contributor to impaired \u03b1\u2010synuclein clearance through autophagy and UPS dysfunction, advancing the understanding of PD's molecular basis.<\/jats:p>","DOI":"10.1002\/adbi.202500274","type":"journal-article","created":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T06:29:13Z","timestamp":1777876153000},"source":"Crossref","is-referenced-by-count":1,"title":["Copper Overload Affects \u03b1\u2010Synuclein Clearance Mechanisms in a Parkinson's Disease In Vitro Model"],"prefix":"10.1002","volume":"10","author":[{"given":"Debora","family":"Musar\u00f2","sequence":"first","affiliation":[{"name":"Laboratory of Clinical Proteomic \u201cV Fazzi\u201d Hospital  Lecce Italy"},{"name":"Laboratory of General and Human Physiology Department of Experimental Medicine University of Salento  Lecce 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