{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T07:47:40Z","timestamp":1782200860488,"version":"3.54.5"},"reference-count":192,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T00:00:00Z","timestamp":1774396800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Parkinson\u2019s disease (PD) is characterized by the progressive degeneration of dopaminergic neurons and the accumulation of \u03b1-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 \u03b1-synuclein misfolding, enhance oxidative stress, and interfere with both the ubiquitin\u2013proteasome system (UPS) and the autophagy\u2013lysosome 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 \u03b1-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.<\/jats:p>","DOI":"10.3390\/ijms27072993","type":"journal-article","created":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T15:05:33Z","timestamp":1774451133000},"page":"2993","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Copper Dyshomeostasis Affects \u03b1-Synuclein Clearance Mechanisms in Parkinson\u2019s Disease: Insights from In Vitro Models and Translational Evidence"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-5551-2206","authenticated-orcid":false,"given":"Debora","family":"Musar\u00f2","sequence":"first","affiliation":[{"name":"Department of Experimental Medicine, University of Salento, Via Lecce\u2014Monteroni, 73100 Lecce, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9228-1158","authenticated-orcid":false,"given":"Marco","family":"Greco","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Salento, Via Lecce\u2014Monteroni, 73100 Lecce, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7608-4026","authenticated-orcid":false,"given":"Martina","family":"Lanza","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Salento, Via Lecce\u2014Monteroni, 73100 Lecce, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0104-4323","authenticated-orcid":false,"given":"Marina","family":"Damato","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Salento, Via Lecce\u2014Monteroni, 73100 Lecce, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0665-4534","authenticated-orcid":false,"given":"Michele","family":"Maffia","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Salento, Via Lecce\u2014Monteroni, 73100 Lecce, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1093\/brain\/122.8.1437","article-title":"The Substantia Nigra of the Human Brain: II. 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