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This study aimed to compare the intra\u2010 and extra\u2010neuronal metal content and the expression of proteins related to metal homeostasis in the substantia nigra (SN) from patients with Parkinson's disease (PD), multiple sclerosis (MS), and control subjects. Metal quantification was performed via ion\u2010beam micro\u2010analysis in neuromelanin\u2010positive neurons and the surrounding tissue. For proteomic analysis, SN tissue lysates were analyzed on a nanoflow chromatography system hyphenated to a hybrid triple\u2010quadrupole time\u2010of\u2010flight mass spectrometer. We found increased amounts of iron in neuromelanin\u2010positive neurons and surrounding tissue in patients with PD and MS compared to controls (4\u2010 to 5\u2010fold higher) that, however, also showed large inter\u2010individual variations. Copper content was systematically lower (\u22122.4\u2010fold) in neuromelanin\u2010positive neurons of PD patients compared with controls, whereas it remained unchanged in MS. Protein\u2013protein interaction (PPI) network analyses revealed clusters related to Fe and Cu homeostasis among PD\u2010deregulated proteins. An enrichment for the term \u201c\n                    <jats:italic>metal homeostasis\u201d<\/jats:italic>\n                    was observed for MS\u2010deregulated proteins. Important deregulated hub proteins included hemopexin and transferrin in PD, and calreticulin and ferredoxin reductase in MS. Our findings show that PD and MS share commonalities in terms of iron accumulation in the SN. Concomitant proteomics experiments revealed PPI networks related to metal homeostasis, substantiating the results of metal quantification.\n                  <\/jats:p>","DOI":"10.1111\/jnc.16040","type":"journal-article","created":{"date-parts":[[2024,1,5]],"date-time":"2024-01-05T03:31:07Z","timestamp":1704425467000},"page":"128-141","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Metal dyshomeostasis in the substantia nigra of patients with Parkinson's disease or multiple sclerosis"],"prefix":"10.1111","volume":"168","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9253-4581","authenticated-orcid":false,"given":"Asuncion","family":"Carmona","sequence":"first","affiliation":[{"name":"University Bordeaux, CNRS  Gradignan France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1354-1239","authenticated-orcid":false,"given":"Eleonora","family":"Carboni","sequence":"additional","affiliation":[{"name":"Department of Neurology University Medical Center G\u00f6ttingen  G\u00f6ttingen Lower\u2010Saxony Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4959-2169","authenticated-orcid":false,"given":"Lucas Caldi","family":"Gomes","sequence":"additional","affiliation":[{"name":"School of Medicine, Klinikum rechts der Isar, Department of Neurology Technical University of Munich  M\u00fcnchen Bavaria Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4539-9380","authenticated-orcid":false,"given":"St\u00e9phane","family":"Roudeau","sequence":"additional","affiliation":[{"name":"University Bordeaux, CNRS  Gradignan France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4077-2852","authenticated-orcid":false,"given":"Fabian","family":"Maass","sequence":"additional","affiliation":[{"name":"Department of Neurology University Medical Center G\u00f6ttingen  G\u00f6ttingen Lower\u2010Saxony Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0946-8166","authenticated-orcid":false,"given":"Christof","family":"Lenz","sequence":"additional","affiliation":[{"name":"Bioanalytical Mass Spectrometry Max Planck Institute for Multidisciplinary Sciences  G\u00f6ttingen Germany"},{"name":"Department of Clinical Chemistry University Medical Center G\u00f6ttingen  G\u00f6ttingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1692-5406","authenticated-orcid":false,"given":"Richard","family":"Ortega","sequence":"additional","affiliation":[{"name":"University Bordeaux, CNRS  Gradignan France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9362-7096","authenticated-orcid":false,"given":"Paul","family":"Lingor","sequence":"additional","affiliation":[{"name":"School of Medicine, Klinikum rechts der Isar, Department of Neurology Technical University of Munich  M\u00fcnchen Bavaria Germany"},{"name":"DZNE, German Center for Neurodegenerative Diseases Research Site Munich  Munich Germany"},{"name":"Munich Cluster for Systems Neurology (SyNergy)  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,1,5]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41531-022-00345-4"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00775-019-01731-9"},{"key":"e_1_2_11_4_1","unstructured":"Alboukadel K. &Fabian M.(2017).Factoextra: Extract and visualize the results of multivariate data analyses. 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