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Although mutations in genes such as PARKIN and LRRK2 have been linked to PD, the idiopathic component of the disease suggests a contribution of environmental risk factors, including metals, such as copper (Cu). Cu overexposure has been reported to cause oxidative stress and neurotoxicity, but its role in neurodegenerative diseases is rarely studied. Using Caenorhabditis elegans (C. elegans) as a model organism for neurotoxicity, we assessed the effects of Cu oversupply in AD and PD models. Our findings reveal that although copper treatment did not induce neurodegeneration in wild-type worms or the AD model, it significantly exacerbated neurodegeneration in the PD-associated mutants PARKIN and LRRK2. These results suggest that genetic predisposition for PD enhances the sensitivity to copper toxicity, highlighting the multifactorial nature of neurodegenerative diseases. Furthermore, our study provides insight into the mechanisms underlying Cu-induced neurotoxicity in PD models, including disruptions in dopamine levels, altered dopamine-dependent behavior and degraded dopaminergic neurons. Overall, our novel findings contribute to a better understanding of the complex interactions between genetic susceptibility, environmental factors, and neurodegenerative disease pathogenesis, emphasizing the importance of a tightly regulated Cu homeostasis in the etiology of PD.<\/jats:p>\n               <jats:p>Copper oversupply exacerbated neurodegeneration in Caenorhabditis elegans models of Parkinson\u2019s disease, highlighting the genetic susceptibility and emphasizing the crucial role of tightly regulated copper homeostasis in Parkinson\u2019s disease pathogenesis.<\/jats:p>","DOI":"10.1093\/toxsci\/kfae092","type":"journal-article","created":{"date-parts":[[2024,7,26]],"date-time":"2024-07-26T08:22:37Z","timestamp":1721982157000},"page":"254-262","source":"Crossref","is-referenced-by-count":7,"title":["Copper-mediated neurotoxicity and genetic vulnerability in the background of neurodegenerative diseases in <i>C. elegans<\/i>"],"prefix":"10.1093","volume":"201","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1650-7899","authenticated-orcid":false,"given":"Ann-Kathrin","family":"Weishaupt","sequence":"first","affiliation":[{"name":"Food Chemistry with Focus on Toxicology, Faculty of Mathematics and Natural Sciences, University of Wuppertal , 42119 Wuppertal,","place":["Germany"]},{"name":"TraceAge\u2014DFG Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly (FOR 2558) , Berlin, Potsdam, Jena, Wuppertal,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lysann","family":"Ruecker","sequence":"additional","affiliation":[{"name":"Food Chemistry with Focus on Toxicology, Faculty of Mathematics and Natural Sciences, University of Wuppertal , 42119 Wuppertal,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Torben","family":"Meiners","sequence":"additional","affiliation":[{"name":"Food Chemistry with Focus on Toxicology, Faculty of Mathematics and Natural Sciences, University of Wuppertal , 42119 Wuppertal,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanja","family":"Schwerdtle","sequence":"additional","affiliation":[{"name":"TraceAge\u2014DFG Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly (FOR 2558) , Berlin, Potsdam, Jena, Wuppertal,","place":["Germany"]},{"name":"German Federal Institute for Risk Assessment (BfR) , 10589 Berlin,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daiana","family":"Silva Avila","sequence":"additional","affiliation":[{"name":"Laboratory of Toxicology and Biochemistry in Caenorhabditis elegans, Universidade Federal do Pampa , 97501-970 Uruguaiana,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Aschner","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology, Albert Einstein College of Medicine , Bronx, NY 10461,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Bornhorst","sequence":"additional","affiliation":[{"name":"Food Chemistry with Focus on Toxicology, Faculty of Mathematics and Natural Sciences, University of Wuppertal , 42119 Wuppertal,","place":["Germany"]},{"name":"TraceAge\u2014DFG Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly (FOR 2558) , Berlin, Potsdam, Jena, Wuppertal,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,7,27]]},"reference":[{"issue":"2","key":"2024092607512057900_kfae092-B1","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines10020288","article-title":"Modeling Alzheimer\u2019s disease in Caenorhabditis elegans","volume":"10","author":"Alvarez","year":"2022","journal-title":"Biomedicines"},{"issue":"22","key":"2024092607512057900_kfae092-B2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms232213850","article-title":"The role of copper homeostasis in brain disease","volume":"23","author":"An","year":"2022","journal-title":"Int J Mol Sci"},{"key":"2024092607512057900_kfae092-B3","doi-asserted-by":"publisher","first-page":"446","DOI":"10.3389\/fnagi.2017.00446","article-title":"Role of copper in the onset of Alzheimer\u2019s disease compared to other metals","volume":"9","author":"Bagheri","year":"2017","journal-title":"Front Aging Neurosci"},{"issue":"10291","key":"2024092607512057900_kfae092-B4","doi-asserted-by":"publisher","first-page":"2284","DOI":"10.1016\/S0140-6736(21)00218-X","article-title":"Parkinson\u2019s disease","volume":"397","author":"Bloem","year":"2021","journal-title":"Lancet"},{"issue":"9","key":"2024092607512057900_kfae092-B5","doi-asserted-by":"publisher","first-page":"1717","DOI":"10.1007\/s11064-008-9610-3","article-title":"Free copper, ferroxidase and SOD1 activities, lipid peroxidation and NO(x) content in the CSF. 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