{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T10:19:07Z","timestamp":1791541147651,"version":"4.3.4"},"reference-count":131,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T00:00:00Z","timestamp":1766966400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T00:00:00Z","timestamp":1766966400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100012352","name":"Universit\u00e0 degli Studi di Milano","doi-asserted-by":"publisher","award":["CRUI"],"award-info":[{"award-number":["CRUI"]}],"id":[{"id":"10.13039\/100012352","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012352","name":"Universit\u00e0 degli Studi di Milano","doi-asserted-by":"publisher","award":["Piano di Sostegno alla Ricerca UNIMI, Linea 2"],"award-info":[{"award-number":["Piano di Sostegno alla Ricerca UNIMI, Linea 2"]}],"id":[{"id":"10.13039\/100012352","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012032","name":"Fondazione Romeo ed Enrica Invernizzi","doi-asserted-by":"publisher","award":["Fondazione Romeo ed Enrica Invernizzi"],"award-info":[{"award-number":["Fondazione Romeo ed Enrica Invernizzi"]}],"id":[{"id":"10.13039\/501100012032","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell. Mol. Life Sci."],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Since the first report in 1972, several studies have documented an association between Parkinson\u2019s disease (PD) and melanoma. Up to 20-fold increased risk of melanoma was reported in PD patients, while a personal\/family history of melanoma was linked to a 1.85-fold PD risk. Neurons and melanocytes, which both derive from the neuroectodermal crest, share biological pathways that may be dysregulated in both diseases. In particular, accumulation of the alpha-synuclein (\u03b1-syn, SNCA) protein, a pathological hallmark of PD, is also observed in melanoma. Indeed, dysregulated \u03b1-syn proteostasis is known to disrupt several biological pathways which can co-incidentally, albeit paradoxically contribute to both neurodegeneration and hyper-proliferative cell growth. These include abnormalities in dopamine (DA), melanin, and iron metabolism, oxidative stress, DNA damage\/repair response, inflammation, as well as alterations in mitochondrial function, and cell-clearing machinery. Although \u03b1-syn depletion was shown to attenuate melanoma cell proliferation and neurodegeneration, it remains unclear whether \u03b1-syn accumulation is a mere culprit of disease, if it represents a common outcome from shared upstream mechanisms, or, finally, a compensatory response to cellular stress. In an effort to elucidate how \u03b1-syn bridges melanomagenesis and the neurodegenerative events of PD, this review discusses specific cellular and molecular pathways related to \u03b1-syn proteostasis, including environmental factors implicated in melanocytic transformation, such as UV radiation. Addressing open questions and establishing novel experimental models remain essential for developing effective therapeutic approaches to target melanoma and PD without overlooking their comorbidity.<\/jats:p>","DOI":"10.1007\/s00018-025-05985-2","type":"journal-article","created":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T13:38:48Z","timestamp":1767015528000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Revisiting the alpha-synuclein paradox in melanoma-Parkinson\u2019s disease connection: more than a tale of two cell fates"],"prefix":"10.1007","volume":"83","author":[{"given":"Jacopo","family":"Aiello","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Zamarato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6614-665X","authenticated-orcid":false,"given":"Claudia","family":"Moscheni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6680-4536","authenticated-orcid":false,"given":"Cristiana","family":"Perrotta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5920-6191","authenticated-orcid":false,"given":"Mario","family":"Clerici","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9535-3359","authenticated-orcid":false,"given":"Daria","family":"Trabattoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3671-4235","authenticated-orcid":false,"given":"Mara","family":"Biasin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0185-2099","authenticated-orcid":false,"given":"Fiona","family":"Limanaqi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,29]]},"reference":[{"key":"5985_CR1","doi-asserted-by":"publisher","first-page":"6469","DOI":"10.1073\/pnas.95.11.6469","volume":"95","author":"MG Spillantini","year":"1998","unstructured":"Spillantini MG, Crowther RA, Jakes R et al (1998) \u03b1-Synuclein in filamentous inclusions of lewy bodies from parkinson\u2019s disease and dementia with lewy bodies. Proc Natl Acad Sci USA 95:6469\u20136473. https:\/\/doi.org\/10.1073\/pnas.95.11.6469","journal-title":"Proc Natl Acad Sci USA"},{"key":"5985_CR2","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1002\/mds.10559","volume":"18","author":"MJ Mart\u00cc","year":"2003","unstructured":"Mart\u00cc MJ, Tolosa E, Campdelacreu J (2003) Clinical overview of the synucleinopathies. Mov Disord 18:21\u201327. https:\/\/doi.org\/10.1002\/mds.10559","journal-title":"Mov Disord"},{"key":"5985_CR3","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a024091","volume":"8","author":"J Burr\u00e9","year":"2018","unstructured":"Burr\u00e9 J, Sharma M, S\u00fcdhof TC (2018) Cell biology and pathophysiology of \u03b1-synuclein. Cold Spring Harb Perspect Med 8:a024091. https:\/\/doi.org\/10.1101\/cshperspect.a024091","journal-title":"Cold Spring Harb Perspect Med"},{"key":"5985_CR4","doi-asserted-by":"publisher","first-page":"598","DOI":"10.2174\/1389203718666171117110028","volume":"19","author":"L Ryskalin","year":"2018","unstructured":"Ryskalin L, Busceti CL, Limanaqi F et al (2018) A focus on the beneficial effects of alpha synuclein and a re-appraisal of synucleinopathies. CPPS 19:598\u2013611. https:\/\/doi.org\/10.2174\/1389203718666171117110028","journal-title":"CPPS"},{"key":"5985_CR5","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a009399","volume":"2","author":"L Stefanis","year":"2012","unstructured":"Stefanis L (2012) Synuclein in Parkinson\u2019s disease. Cold Spring Harb Perspect Med 2:a009399\u2013a009399. https:\/\/doi.org\/10.1101\/cshperspect.a009399","journal-title":"Cold Spring Harb Perspect Med"},{"key":"5985_CR6","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-014-0176-9","author":"RM Gir\u00e1ldez-P\u00e9rez","year":"2014","unstructured":"Gir\u00e1ldez-P\u00e9rez RM, Antol\u00edn-Vallesp\u00edn M, Mu\u00f1oz MD, S\u00e1nchez-Capelo A (2014) Models of \u03b1-synuclein aggregation in Parkinson\u2019s disease. Acta Neuropathol Commun. https:\/\/doi.org\/10.1186\/s40478-014-0176-9","journal-title":"Acta Neuropathol Commun"},{"key":"5985_CR7","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1385\/JMN:22:3:199","volume":"22","author":"S Baltic","year":"2004","unstructured":"Baltic S, Perovic M, Mladenovic A et al (2004) \u0391-synuclein is expressed in different tissues during human fetal development. JMN 22:199\u2013204. https:\/\/doi.org\/10.1385\/JMN:22:3:199","journal-title":"JMN"},{"key":"5985_CR8","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1159\/000112832","volume":"5","author":"R Barbour","year":"2008","unstructured":"Barbour R, Kling K, Anderson JP et al (2008) Red blood cells are the major source of Alpha-synuclein in blood. Neurodegener Dis 5:55\u201359. https:\/\/doi.org\/10.1159\/000112832","journal-title":"Neurodegener Dis"},{"key":"5985_CR9","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2024.1421360","author":"F Limanaqi","year":"2024","unstructured":"Limanaqi F, Zecchini S, Ogno P et al (2024) Alpha-synuclein shapes monocyte and macrophage cell biology and functions by bridging alterations of autophagy and inflammatory pathways. Front Cell Dev Biol. https:\/\/doi.org\/10.3389\/fcell.2024.1421360","journal-title":"Front Cell Dev Biol"},{"key":"5985_CR10","doi-asserted-by":"publisher","DOI":"10.1186\/s40659-023-00482-x","volume":"57","author":"F Limanaqi","year":"2024","unstructured":"Limanaqi F, Zecchini S, Saulle I et al (2024) Alpha-synuclein dynamics bridge type-I interferon response and SARS-CoV-2 replication in peripheral cells. Biol Res 57:2. https:\/\/doi.org\/10.1186\/s40659-023-00482-x","journal-title":"Biol Res"},{"key":"5985_CR11","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2019.e02590","volume":"5","author":"Y Pei","year":"2019","unstructured":"Pei Y, Maitta RW (2019) Alpha synuclein in hematopoiesis and immunity. Heliyon 5:e02590. https:\/\/doi.org\/10.1016\/j.heliyon.2019.e02590","journal-title":"Heliyon"},{"key":"5985_CR12","doi-asserted-by":"publisher","first-page":"1599","DOI":"10.1007\/s00702-021-02364-6","volume":"128","author":"F Biagioni","year":"2021","unstructured":"Biagioni F, Ferese R, Giorgi FS et al (2021) An attempt to dissect a peripheral marker based on cell pathology in Parkinson\u2019s disease. J Neural Transm 128:1599\u20131610. https:\/\/doi.org\/10.1007\/s00702-021-02364-6","journal-title":"J Neural Transm"},{"key":"5985_CR13","doi-asserted-by":"publisher","DOI":"10.3390\/biom13081263","volume":"13","author":"FJ Jim\u00e9nez-Jim\u00e9nez","year":"2023","unstructured":"Jim\u00e9nez-Jim\u00e9nez FJ, Alonso-Navarro H, Garc\u00eda-Mart\u00edn E et al (2023) Alpha-synuclein in peripheral tissues as a possible marker for neurological diseases and other medical conditions. Biomolecules 13:1263. https:\/\/doi.org\/10.3390\/biom13081263","journal-title":"Biomolecules"},{"key":"5985_CR14","doi-asserted-by":"publisher","first-page":"1452","DOI":"10.1002\/mds.27794","volume":"34","author":"K Tsukita","year":"2019","unstructured":"Tsukita K, Sakamaki-Tsukita H, Tanaka K et al (2019) Value of in vivo \u03b1\u2010synuclein deposits in parkinson\u2019s disease: A systematic review and meta\u2010analysis. Mov Disord 34:1452\u20131463. https:\/\/doi.org\/10.1002\/mds.27794","journal-title":"Mov Disord"},{"key":"5985_CR15","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1002\/ana.24567","volume":"79","author":"V Donadio","year":"2016","unstructured":"Donadio V, Incensi A, Piccinini C et al (2016) Skin nerve misfolded \u03b1-synuclein in pure autonomic failure and Parkinson disease. Ann Neurol 79:306\u2013316. https:\/\/doi.org\/10.1002\/ana.24567","journal-title":"Ann Neurol"},{"key":"5985_CR16","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2024.0792","volume":"331","author":"CH Gibbons","year":"2024","unstructured":"Gibbons CH, Levine T, Adler C et al (2024) Skin biopsy detection of phosphorylated \u03b1-synuclein in patients with synucleinopathies. JAMA 331:1298. https:\/\/doi.org\/10.1001\/jama.2024.0792","journal-title":"JAMA"},{"key":"5985_CR17","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/j.parkreldis.2019.03.003","volume":"64","author":"A Kuzkina","year":"2019","unstructured":"Kuzkina A, Schulmeyer L, Monoranu C-M et al (2019) The aggregation state of \u03b1-synuclein deposits in dermal nerve fibers of patients with Parkinson\u2019s disease resembles that in the brain. Parkinsonism Relat Disord 64:66\u201372. https:\/\/doi.org\/10.1016\/j.parkreldis.2019.03.003","journal-title":"Parkinsonism Relat Disord"},{"key":"5985_CR18","doi-asserted-by":"publisher","first-page":"724","DOI":"10.1002\/mdc3.12494","volume":"4","author":"I Rodriguez-Leyva","year":"2017","unstructured":"Rodriguez-Leyva I, Chi\u2010Ahumada E, Mej\u00eda M et al (2017) The presence of Alpha\u2010synuclein in skin from melanoma and patients with parkinson\u2019s disease. Mov Disord Clin Pract 4:724\u2013732. https:\/\/doi.org\/10.1002\/mdc3.12494","journal-title":"Mov Disord Clin Pract"},{"key":"5985_CR19","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1002\/acn3.285","volume":"3","author":"I Rodr\u00edguez-Leyva","year":"2016","unstructured":"Rodr\u00edguez-Leyva I, Chi\u2010Ahumada EG, Carrizales J et al (2016) Parkinson disease and progressive supranuclear palsy: protein expression in skin. Ann Clin Transl Neurol 3:191\u2013199. https:\/\/doi.org\/10.1002\/acn3.285","journal-title":"Ann Clin Transl Neurol"},{"key":"5985_CR20","doi-asserted-by":"publisher","first-page":"385","DOI":"10.3233\/jpd-171263","volume":"8","author":"A Bose","year":"2018","unstructured":"Bose A, Petsko GA, Eliezer D (2018) Parkinson\u2019s disease and melanoma: co-occurrence and mechanisms. J Parkinsons Dis 8:385\u2013398. https:\/\/doi.org\/10.3233\/jpd-171263","journal-title":"J Parkinsons Dis"},{"key":"5985_CR21","first-page":"556","volume":"93","author":"JL Skibba","year":"1972","unstructured":"Skibba JL, Pinckley J, Gilbert EF, Johnson RO (1972) Multiple primary melanoma following administration of levodopa. Arch Pathol 93:556\u2013561","journal-title":"Arch Pathol"},{"key":"5985_CR22","doi-asserted-by":"publisher","first-page":"1489","DOI":"10.1002\/mds.28655","volume":"36","author":"DN Dean","year":"2021","unstructured":"Dean DN, Lee JC (2021) Linking parkinson\u2019s disease and melanoma: interplay between \u03b1-Synuclein and Pmel17 amyloid formation. Mov Disord 36:1489\u20131498. https:\/\/doi.org\/10.1002\/mds.28655","journal-title":"Mov Disord"},{"key":"5985_CR23","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1007\/s13760-019-01195-3","volume":"119","author":"A Bougea","year":"2019","unstructured":"Bougea A, Spantideas N, Katoulis A, Stefanis L (2019) Levodopa-induced skin disorders in patients with Parkinson disease: a systematic literature review approach. Acta Neurol Belg 119:325\u2013336. https:\/\/doi.org\/10.1007\/s13760-019-01195-3","journal-title":"Acta Neurol Belg"},{"key":"5985_CR24","doi-asserted-by":"publisher","first-page":"1252","DOI":"10.1002\/mds.21397","volume":"22","author":"JH Olsen","year":"2007","unstructured":"Olsen JH, Tangerud K, Wermuth L et al (2007) Treatment with levodopa and risk for malignant melanoma. Mov Disord 22:1252\u20131257. https:\/\/doi.org\/10.1002\/mds.21397","journal-title":"Mov Disord"},{"key":"5985_CR25","doi-asserted-by":"publisher","first-page":"1286","DOI":"10.1212\/wnl.0b013e3181bd13a1","volume":"73","author":"X Gao","year":"2009","unstructured":"Gao X, Simon KC, Han J et al (2009) Family history of melanoma and Parkinson disease risk. Neurology 73:1286\u20131291. https:\/\/doi.org\/10.1212\/wnl.0b013e3181bd13a1","journal-title":"Neurology"},{"key":"5985_CR26","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0010481","volume":"5","author":"Y Matsuo","year":"2010","unstructured":"Matsuo Y, Kamitani T (2010) Parkinson\u2019s disease-related protein, \u03b1-synuclein, in malignant melanoma. PLoS One 5:e10481. https:\/\/doi.org\/10.1371\/journal.pone.0010481","journal-title":"PLoS One"},{"key":"5985_CR27","doi-asserted-by":"publisher","first-page":"6656","DOI":"10.1523\/JNEUROSCI.0278-19.2019","volume":"39","author":"CR Bye","year":"2019","unstructured":"Bye CR, Rytova V, Alsanie WF et al (2019) Axonal growth of midbrain dopamine neurons is modulated by the cell adhesion molecule ALCAM through Trans -heterophilic interactions with L1cam, Chl1, and semaphorins. J Neurosci 39:6656\u20136667. https:\/\/doi.org\/10.1523\/JNEUROSCI.0278-19.2019","journal-title":"J Neurosci"},{"key":"5985_CR28","doi-asserted-by":"publisher","DOI":"10.3390\/cells11193085","volume":"11","author":"II Stoyanova","year":"2022","unstructured":"Stoyanova II, Lutz D (2022) Functional diversity of neuronal cell adhesion and recognition molecule L1CAM through proteolytic cleavage. Cells 11:3085. https:\/\/doi.org\/10.3390\/cells11193085","journal-title":"Cells"},{"key":"5985_CR29","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-36451-3","author":"N Gajendran","year":"2023","unstructured":"Gajendran N, Rajasekaran S, Witt SN (2023) Knocking out alpha-synuclein in melanoma cells downregulates L1CAM and decreases motility. Sci Rep. https:\/\/doi.org\/10.1038\/s41598-023-36451-3","journal-title":"Sci Rep"},{"key":"5985_CR30","doi-asserted-by":"publisher","first-page":"1433","DOI":"10.1093\/hmg\/ddaf096","volume":"34","author":"NM Aloy","year":"2025","unstructured":"Aloy NM, Ericsson M, Hartman B, Witt SN (2025) Alpha-synuclein modulates the positioning of endolysosomes in melanoma cells. Hum Mol Genet 34:1433\u20131445. https:\/\/doi.org\/10.1093\/hmg\/ddaf096","journal-title":"Hum Mol Genet"},{"key":"5985_CR31","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2025.101999","volume":"6","author":"S Yan","year":"2025","unstructured":"Yan S, Zhang W, Li X et al (2025) Single extracellular vesicle detection assay identifies membrane-associated \u03b1-synuclein as an early-stage biomarker in Parkinson\u2019s disease. Cell Rep Med 6:101999. https:\/\/doi.org\/10.1016\/j.xcrm.2025.101999","journal-title":"Cell Rep Med"},{"key":"5985_CR32","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0045183","volume":"7","author":"T Pan","year":"2012","unstructured":"Pan T, Zhu J, Hwu W-J, Jankovic J (2012) The role of Alpha-Synuclein in melanin synthesis in melanoma and dopaminergic neuronal cells. PLoS One 7:e45183. https:\/\/doi.org\/10.1371\/journal.pone.0045183","journal-title":"PLoS One"},{"key":"5985_CR33","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1111\/pcmr.13165","volume":"37","author":"M Snyman","year":"2024","unstructured":"Snyman M, Walsdorf RE, Wix SN, Gill JG (2024) The metabolism of melanin synthesis\u2014from melanocytes to melanoma. Pigment Cell Melanoma Res 37:438\u2013452. https:\/\/doi.org\/10.1111\/pcmr.13165","journal-title":"Pigment Cell Melanoma Res"},{"key":"5985_CR34","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1016\/j.gde.2017.05.001","volume":"45","author":"R Tadokoro","year":"2017","unstructured":"Tadokoro R, Takahashi Y (2017) Intercellular transfer of organelles during body pigmentation. Curr Opin Genet Dev 45:132\u2013138. https:\/\/doi.org\/10.1016\/j.gde.2017.05.001","journal-title":"Curr Opin Genet Dev"},{"key":"5985_CR35","doi-asserted-by":"publisher","DOI":"10.3390\/ijms17071144","volume":"17","author":"S D\u2019Mello","year":"2016","unstructured":"D\u2019Mello S, Finlay G, Baguley B, Askarian-Amiri M (2016) Signaling pathways in melanogenesis. IJMS 17:1144. https:\/\/doi.org\/10.3390\/ijms17071144","journal-title":"IJMS"},{"key":"5985_CR36","doi-asserted-by":"publisher","first-page":"762","DOI":"10.1111\/pcmr.12985","volume":"34","author":"PR Upadhyay","year":"2021","unstructured":"Upadhyay PR, Ho T, Abdel-Malek ZA (2021) Participation of keratinocyte\u2010 and fibroblast\u2010derived factors in melanocyte homeostasis, the response to UV, and pigmentary disorders. Pigment Cell Melanoma Res 34:762\u2013776. https:\/\/doi.org\/10.1111\/pcmr.12985","journal-title":"Pigment Cell Melanoma Res"},{"key":"5985_CR37","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22094466","volume":"22","author":"H Moreiras","year":"2021","unstructured":"Moreiras H, Seabra MC, Barral DC (2021) Melanin transfer in the epidermis: the pursuit of skin pigmentation control mechanisms. IJMS 22:4466. https:\/\/doi.org\/10.3390\/ijms22094466","journal-title":"IJMS"},{"key":"5985_CR38","doi-asserted-by":"publisher","DOI":"10.3390\/cells11132087","volume":"11","author":"N Rachinger","year":"2022","unstructured":"Rachinger N, Mittag N, B\u00f6hme-Sch\u00e4fer I et al (2022) Alpha-synuclein and its role in melanocytes. Cells 11:2087. https:\/\/doi.org\/10.3390\/cells11132087","journal-title":"Cells"},{"key":"5985_CR39","doi-asserted-by":"publisher","first-page":"22671","DOI":"10.1073\/pnas.2009702117","volume":"117","author":"DN Dean","year":"2020","unstructured":"Dean DN, Lee JC (2020) Defining an amyloid link between parkinson\u2019s disease and melanoma. Proc Natl Acad Sci USA 117:22671\u201322673. https:\/\/doi.org\/10.1073\/pnas.2009702117","journal-title":"Proc Natl Acad Sci USA"},{"key":"5985_CR40","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2015.169","volume":"6","author":"JC Koch","year":"2015","unstructured":"Koch JC, Bitow F, Haack J et al (2015) Alpha-synuclein affects neurite morphology, autophagy, vesicle transport and axonal degeneration in CNS neurons. Cell Death Dis 6:e1811\u2013e1811. https:\/\/doi.org\/10.1038\/cddis.2015.169","journal-title":"Cell Death Dis"},{"key":"5985_CR41","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23031812","volume":"23","author":"L Seebauer","year":"2022","unstructured":"Seebauer L, Schneider Y, Drobny A et al (2022) Interaction of alpha synuclein and microtubule organization is linked to impaired neuritic integrity in Parkinson\u2019s patient-derived neuronal cells. IJMS 23:1812. https:\/\/doi.org\/10.3390\/ijms23031812","journal-title":"IJMS"},{"key":"5985_CR42","doi-asserted-by":"publisher","first-page":"1663","DOI":"10.1126\/science.1195227","volume":"329","author":"J Burr\u00e9","year":"2010","unstructured":"Burr\u00e9 J, Sharma M, Tsetsenis T et al (2010) \u03b1-Synuclein promotes SNARE-Complex assembly in vivo and in vitro. Science 329:1663\u20131667. https:\/\/doi.org\/10.1126\/science.1195227","journal-title":"Science"},{"key":"5985_CR43","doi-asserted-by":"publisher","first-page":"175","DOI":"10.3233\/jpd-2011-11025","volume":"1","author":"SK Mak","year":"2011","unstructured":"Mak SK, Tewari D, Tetrud JW et al (2011) Mitochondrial dysfunction in skin fibroblasts from a Parkinson\u2019s disease patient with an alpha-Synuclein triplication. J Parkinsons Dis 1:175\u2013183. https:\/\/doi.org\/10.3233\/jpd-2011-11025","journal-title":"J Parkinsons Dis"},{"key":"5985_CR44","doi-asserted-by":"publisher","DOI":"10.1186\/2047-9158-2-20","volume":"2","author":"N Braidy","year":"2013","unstructured":"Braidy N, Gai W-P, Xu YH et al (2013) Uptake and mitochondrial dysfunction of alpha-synuclein in human astrocytes, cortical neurons and fibroblasts. Transl Neurodegener 2:20. https:\/\/doi.org\/10.1186\/2047-9158-2-20","journal-title":"Transl Neurodegener"},{"key":"5985_CR45","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1016\/j.neurobiolaging.2022.02.010","volume":"113","author":"JT Oliveira","year":"2022","unstructured":"Oliveira JT, Dakic V, Vit\u00f3ria G et al (2022) Oligomeric \u03b1-synuclein induces skin degeneration in reconstructed human epidermis. Neurobiol Aging 113:108\u2013117. https:\/\/doi.org\/10.1016\/j.neurobiolaging.2022.02.010","journal-title":"Neurobiol Aging"},{"key":"5985_CR46","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1111\/j.1600-0749.1987.tb00403.x","volume":"1","author":"NG Lindquist","year":"1987","unstructured":"Lindquist NG, Larsson BS, Lyd\u00e9n-Sokolowski A (1987) Neuromelanin and its possible protective and destructive properties. Pigment Cell Res 1:133\u2013136. https:\/\/doi.org\/10.1111\/j.1600-0749.1987.tb00403.x","journal-title":"Pigment Cell Res"},{"key":"5985_CR47","doi-asserted-by":"publisher","first-page":"1122","DOI":"10.3390\/biom5021122","volume":"5","author":"S Xu","year":"2015","unstructured":"Xu S, Chan P (2015) Interaction between neuromelanin and alpha-synuclein in parkinson\u2019s disease. Biomolecules 5:1122\u20131142. https:\/\/doi.org\/10.3390\/biom5021122","journal-title":"Biomolecules"},{"key":"5985_CR48","doi-asserted-by":"publisher","first-page":"1866","DOI":"10.1111\/j.1471-4159.2008.05541.x","volume":"106","author":"L Zecca","year":"2008","unstructured":"Zecca L, Casella L, Albertini A et al (2008) Neuromelanin can protect against iron-mediated oxidative damage in system modeling iron overload of brain aging and Parkinson\u2019s disease. J Neurochem 106:1866\u20131875. https:\/\/doi.org\/10.1111\/j.1471-4159.2008.05541.x","journal-title":"J Neurochem"},{"key":"5985_CR49","doi-asserted-by":"publisher","first-page":"11869","DOI":"10.1073\/pnas.97.22.11869","volume":"97","author":"D Sulzer","year":"2000","unstructured":"Sulzer D, Bogulavsky J, Larsen KE et al (2000) Neuromelanin biosynthesis is driven by excess cytosolic catecholamines not accumulated by synaptic vesicles. Proc Natl Acad Sci USA 97:11869\u201311874. https:\/\/doi.org\/10.1073\/pnas.97.22.11869","journal-title":"Proc Natl Acad Sci USA"},{"key":"5985_CR50","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1016\/j.tins.2025.04.005","volume":"48","author":"A Filimontseva","year":"2025","unstructured":"Filimontseva A, Fu Y, Vila M, Halliday GM (2025) Neuromelanin and selective neuronal vulnerability to Parkinson\u2019s disease. Trends Neurosci 48:445\u2013459. https:\/\/doi.org\/10.1016\/j.tins.2025.04.005","journal-title":"Trends Neurosci"},{"key":"5985_CR51","doi-asserted-by":"publisher","first-page":"1575","DOI":"10.1007\/s00702-011-0636-3","volume":"118","author":"Q Xuan","year":"2011","unstructured":"Xuan Q, Xu S-L, Lu D-H et al (2011) Increase expression of \u03b1-synuclein in aged human brain associated with neuromelanin accumulation. J Neural Transm 118:1575\u20131583. https:\/\/doi.org\/10.1007\/s00702-011-0636-3","journal-title":"J Neural Transm"},{"key":"5985_CR52","doi-asserted-by":"publisher","first-page":"2654","DOI":"10.1093\/brain\/awh584","volume":"128","author":"GM Halliday","year":"2005","unstructured":"Halliday GM, Ophof A, Broe M et al (2005) \u03b1-Synuclein redistributes to neuromelanin lipid in the substantia Nigra early in parkinson\u2019s disease. Brain 128:2654\u20132664. https:\/\/doi.org\/10.1093\/brain\/awh584","journal-title":"Brain"},{"key":"5985_CR53","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1016\/S0197-0186(02)00161-4","volume":"42","author":"M Fasano","year":"2003","unstructured":"Fasano M, Giraudo S, Coha S et al (2003) Residual substantia nigra neuromelanin in Parkinson\u2019s disease is cross-linked to \u03b1-synuclein. Neurochem Int 42:603\u2013606. https:\/\/doi.org\/10.1016\/S0197-0186(02)00161-4","journal-title":"Neurochem Int"},{"key":"5985_CR54","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-08858-y","volume":"10","author":"I Carballo-Carbajal","year":"2019","unstructured":"Carballo-Carbajal I, Laguna A, Romero-Gim\u00e9nez J et al (2019) Brain tyrosinase overexpression implicates age-dependent neuromelanin production in Parkinson\u2019s disease pathogenesis. Nat Commun 10:973. https:\/\/doi.org\/10.1038\/s41467-019-08858-y","journal-title":"Nat Commun"},{"key":"5985_CR55","doi-asserted-by":"publisher","first-page":"1040","DOI":"10.1093\/brain\/awac445","volume":"146","author":"M Gonzalez-Sepulveda","year":"2023","unstructured":"Gonzalez-Sepulveda M, Compte J, Cuadros T et al (2023) In vivo reduction of age-dependent neuromelanin accumulation mitigates features of parkinson\u2019s disease. Brain 146:1040\u20131052. https:\/\/doi.org\/10.1093\/brain\/awac445","journal-title":"Brain"},{"key":"5985_CR56","doi-asserted-by":"publisher","first-page":"5000","DOI":"10.1093\/brain\/awad331","volume":"146","author":"J Chocarro","year":"2023","unstructured":"Chocarro J, Rico AJ, Ariznabarreta G et al (2023) Neuromelanin accumulation drives endogenous synucleinopathy in non-human primates. Brain 146:5000\u20135014. https:\/\/doi.org\/10.1093\/brain\/awad331","journal-title":"Brain"},{"key":"5985_CR57","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-025-08544-4","volume":"8","author":"L Blasco-Agell","year":"2025","unstructured":"Blasco-Agell L, Pons-Espinal M, Testa V et al (2025) LRRK2-mutant microglia and neuromelanin synergize to drive dopaminergic neurodegeneration in an iPSC-based parkinson\u2019s disease model. Commun Biol 8:1203. https:\/\/doi.org\/10.1038\/s42003-025-08544-4","journal-title":"Commun Biol"},{"key":"5985_CR58","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-53168-7","volume":"15","author":"A Laguna","year":"2024","unstructured":"Laguna A, Pe\u00f1uelas N, Gonzalez-Sepulveda M et al (2024) Modelling human neuronal catecholaminergic pigmentation in rodents recapitulates age-related neurodegenerative deficits. Nat Commun 15:8819. https:\/\/doi.org\/10.1038\/s41467-024-53168-7","journal-title":"Nat Commun"},{"key":"5985_CR59","doi-asserted-by":"publisher","DOI":"10.1093\/braincomms\/fcaf204","volume":"7","author":"J-B P\u00e9rot","year":"2025","unstructured":"P\u00e9rot J-B, Ruze A, Gaurav R et al (2025) Longitudinal neuromelanin changes in prodromal and early Parkinson\u2019s disease in humans and rat model. Brain Commun 7:fcaf204. https:\/\/doi.org\/10.1093\/braincomms\/fcaf204","journal-title":"Brain Commun"},{"key":"5985_CR60","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms1893","author":"FP Noonan","year":"2012","unstructured":"Noonan FP, Zaidi MR, Wolnicka-Glubisz A et al (2012) Melanoma induction by ultraviolet A but not ultraviolet B radiation requires melanin pigment. Nat Commun. https:\/\/doi.org\/10.1038\/ncomms1893","journal-title":"Nat Commun"},{"key":"5985_CR61","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13225791","volume":"13","author":"E Catalani","year":"2021","unstructured":"Catalani E, Giovarelli M, Zecchini S et al (2021) Oxidative stress and autophagy as key targets in melanoma cell fate. Cancers (Basel) 13:5791. https:\/\/doi.org\/10.3390\/cancers13225791","journal-title":"Cancers (Basel)"},{"key":"5985_CR62","doi-asserted-by":"publisher","unstructured":"Turriani E, L\u00e1zaro DF, Ryazanov S et al (2017) Treatment with diphenyl\u2013pyrazole compound anle138b\/c reveals that \u03b1-synuclein protects melanoma cells from autophagic cell death. Proc Natl Acad Sci USA 114. https:\/\/doi.org\/10.1073\/pnas.1700200114","DOI":"10.1073\/pnas.1700200114"},{"key":"5985_CR63","doi-asserted-by":"publisher","DOI":"10.1155\/nri\/1119424","author":"ME Jimenez-Capdeville","year":"2025","unstructured":"Jimenez-Capdeville ME, Chi-Ahumada E, Garc\u00eda-Ortega F et al (2025) Nuclear Alpha-synuclein in Parkinson\u2019s disease and the malignant transformation in melanoma. Neurol Res Int. https:\/\/doi.org\/10.1155\/nri\/1119424","journal-title":"Neurol Res Int"},{"key":"5985_CR64","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1242\/jcs.122093","volume":"126","author":"BR Lee","year":"2013","unstructured":"Lee BR, Matsuo Y, Cashikar AG, Kamitani T (2013) Role of Ser129 phosphorylation of \u03b1-synuclein in melanoma cells. J Cell Sci 126:696\u2013704. https:\/\/doi.org\/10.1242\/jcs.122093","journal-title":"J Cell Sci"},{"key":"5985_CR65","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1097\/cmr.0000000000000982","volume":"34","author":"C Fokken","year":"2024","unstructured":"Fokken C, Silbern I, Shomroni O et al (2024) Interfering with aggregated \u03b1-synuclein in advanced melanoma leads to a major upregulation of MHC class II proteins. Melanoma Res 34:393\u2013407. https:\/\/doi.org\/10.1097\/cmr.0000000000000982","journal-title":"Melanoma Res"},{"key":"5985_CR66","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.6900","author":"A Quesnel","year":"2024","unstructured":"Quesnel A, Martin LD, Tarzi C et al (2024) Uncovering potential diagnostic and pathophysiological roles of \u03b1-synuclein and DJ\u20101 in melanoma. Cancer Med. https:\/\/doi.org\/10.1002\/cam4.6900","journal-title":"Cancer Med"},{"key":"5985_CR67","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0019622","volume":"6","author":"E Israeli","year":"2011","unstructured":"Israeli E, Yakunin E, Zarbiv Y et al (2011) \u03b1-Synuclein expression selectively affects tumorigenesis in mice modeling Parkinson\u2019s disease. PLoS One 6:e19622. https:\/\/doi.org\/10.1371\/journal.pone.0019622","journal-title":"PLoS One"},{"key":"5985_CR68","doi-asserted-by":"publisher","first-page":"150631","DOI":"10.1016\/j.bbrc.2024.150631","volume":"734","author":"NM Aloy","year":"2024","unstructured":"Aloy NM, Coughlan C, Graner MW, Witt SN (2024) Possible regulation of the immune modulator tetraspanin CD81 by alpha-synuclein in melanoma. Biochem Biophys Res Commun 734:150631. https:\/\/doi.org\/10.1016\/j.bbrc.2024.150631","journal-title":"Biochem Biophys Res Commun"},{"key":"5985_CR69","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-024-78777-6","volume":"14","author":"S Rajasekaran","year":"2024","unstructured":"Rajasekaran S, Cheng S, Gajendran N et al (2024) Transcriptomic analysis of melanoma cells reveals an association of \u03b1-synuclein with regulation of the inflammatory response. Sci Rep 14:27140. https:\/\/doi.org\/10.1038\/s41598-024-78777-6","journal-title":"Sci Rep"},{"key":"5985_CR70","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-84443-y","author":"S Shekoohi","year":"2021","unstructured":"Shekoohi S, Rajasekaran S, Patel D et al (2021) Knocking out alpha-synuclein in melanoma cells dysregulates cellular iron metabolism and suppresses tumor growth. Sci Rep. https:\/\/doi.org\/10.1038\/s41598-021-84443-y","journal-title":"Sci Rep"},{"key":"5985_CR71","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adq2519","author":"MR Arnold","year":"2025","unstructured":"Arnold MR, Cohn GM, Oxe KC et al (2025) Alpha-synuclein regulates nucleolar DNA double-strand break repair in melanoma. Sci Adv. https:\/\/doi.org\/10.1126\/sciadv.adq2519","journal-title":"Sci Adv"},{"key":"5985_CR72","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202301489r","author":"E Niederberger","year":"2023","unstructured":"Niederberger E, M\u00f6ller M, Mungo E et al (2023) Distinct molecular mechanisms contribute to the reduction of melanoma growth and tumor pain after systemic and local depletion of alpha-synuclein in mice. FASEB J. https:\/\/doi.org\/10.1096\/fj.202301489r","journal-title":"FASEB J"},{"key":"5985_CR73","doi-asserted-by":"crossref","unstructured":"Arnold MR, Chen S, Unni VK (2024) Alpha-synuclein knockout impairs melanoma development and alters DNA damage repair in the TG3 mouse model in a sex-dependent manner","DOI":"10.1101\/2024.12.01.626256"},{"key":"5985_CR74","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcn.2022.103702","volume":"119","author":"J Prahl","year":"2022","unstructured":"Prahl J, Pierce SE, Coetzee GA, Tyson T (2022) Alpha-synuclein negatively controls cell proliferation in dopaminergic neurons. Mol Cell Neurosci 119:103702. https:\/\/doi.org\/10.1016\/j.mcn.2022.103702","journal-title":"Mol Cell Neurosci"},{"key":"5985_CR75","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1016\/j.cell.2005.09.028","volume":"123","author":"S Chandra","year":"2005","unstructured":"Chandra S, Gallardo G, Fern\u00e1ndez-Chac\u00f3n R et al (2005) \u0391-Synuclein cooperates with CSP\u03b1 in preventing neurodegeneration. Cell 123:383\u2013396. https:\/\/doi.org\/10.1016\/j.cell.2005.09.028","journal-title":"Cell"},{"key":"5985_CR76","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1016\/j.freeradbiomed.2016.06.025","volume":"97","author":"S Baksi","year":"2016","unstructured":"Baksi S, Tripathi AK, Singh N (2016) Alpha-synuclein modulates retinal iron homeostasis by facilitating the uptake of transferrin-bound iron: implications for visual manifestations of Parkinson\u2019s disease. Free Radic Biol Med 97:292\u2013306. https:\/\/doi.org\/10.1016\/j.freeradbiomed.2016.06.025","journal-title":"Free Radic Biol Med"},{"key":"5985_CR77","doi-asserted-by":"publisher","first-page":"1514","DOI":"10.1093\/hmg\/ddy059","volume":"27","author":"D Patel","year":"2018","unstructured":"Patel D, Xu C, Nagarajan S et al (2018) Alpha-synuclein inhibits Snx3\u2013retromer-mediated retrograde recycling of iron transporters in S. cerevisiae and C. elegans models of parkinson\u2019s disease. Hum Mol Genet 27:1514\u20131532. https:\/\/doi.org\/10.1093\/hmg\/ddy059","journal-title":"Hum Mol Genet"},{"key":"5985_CR78","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1016\/j.expneurol.2017.11.010","volume":"300","author":"AS Harms","year":"2018","unstructured":"Harms AS, Thome AD, Yan Z et al (2018) Peripheral monocyte entry is required for alpha-Synuclein induced inflammation and neurodegeneration in a model of Parkinson disease. Exp Neurol 300:179\u2013187. https:\/\/doi.org\/10.1016\/j.expneurol.2017.11.010","journal-title":"Exp Neurol"},{"key":"5985_CR79","doi-asserted-by":"publisher","unstructured":"Brochard V, Combadi\u00e8re B, Prigent A et al (2008) Infiltration of CD4\u2009+\u2009lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J Clin Invest. https:\/\/doi.org\/10.1172\/jci36470","DOI":"10.1172\/jci36470"},{"key":"5985_CR80","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms4633","author":"C Cebri\u00e1n","year":"2014","unstructured":"Cebri\u00e1n C, Zucca FA, Mauri P et al (2014) MHC-I expression renders catecholaminergic neurons susceptible to T-cell-mediated degeneration. Nat Commun. https:\/\/doi.org\/10.1038\/ncomms4633","journal-title":"Nat Commun"},{"key":"5985_CR81","doi-asserted-by":"publisher","first-page":"656","DOI":"10.1038\/nature22815","volume":"546","author":"D Sulzer","year":"2017","unstructured":"Sulzer D, Alcalay RN, Garretti F et al (2017) T cells from patients with Parkinson\u2019s disease recognize \u03b1-synuclein peptides. Nature 546:656\u2013661. https:\/\/doi.org\/10.1038\/nature22815","journal-title":"Nature"},{"key":"5985_CR82","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-47227-z","author":"AJ Schaser","year":"2019","unstructured":"Schaser AJ, Osterberg VR, Dent SE et al (2019) Alpha-synuclein is a DNA binding protein that modulates DNA repair with implications for lewy body disorders. Sci Rep. https:\/\/doi.org\/10.1038\/s41598-019-47227-z","journal-title":"Sci Rep"},{"key":"5985_CR83","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.110090","volume":"38","author":"MM Alam","year":"2022","unstructured":"Alam MM, Yang D, Li X-Q et al (2022) Alpha synuclein, the culprit in Parkinson disease, is required for normal immune function. Cell Rep 38:110090. https:\/\/doi.org\/10.1016\/j.celrep.2021.110090","journal-title":"Cell Rep"},{"key":"5985_CR84","doi-asserted-by":"publisher","first-page":"3622","DOI":"10.1093\/brain\/awac192","volume":"145","author":"B Monogue","year":"2022","unstructured":"Monogue B, Chen Y, Sparks H et al (2022) Alpha-synuclein supports type 1 interferon signalling in neurons and brain tissue. Brain 145:3622\u20133636. https:\/\/doi.org\/10.1093\/brain\/awac192","journal-title":"Brain"},{"key":"5985_CR85","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1016\/j.imbio.2015.10.002","volume":"221","author":"A Shameli","year":"2016","unstructured":"Shameli A, Xiao W, Zheng Y et al (2016) A critical role for alpha-synuclein in development and function of T lymphocytes. Immunobiology 221:333\u2013340. https:\/\/doi.org\/10.1016\/j.imbio.2015.10.002","journal-title":"Immunobiology"},{"key":"5985_CR86","doi-asserted-by":"publisher","first-page":"836","DOI":"10.1016\/j.imbio.2014.07.014","volume":"219","author":"W Xiao","year":"2014","unstructured":"Xiao W, Shameli A, Harding CV et al (2014) Late stages of hematopoiesis and B cell lymphopoiesis are regulated by \u03b1-synuclein, a key player in parkinson\u2019s disease. Immunobiology 219:836\u2013844. https:\/\/doi.org\/10.1016\/j.imbio.2014.07.014","journal-title":"Immunobiology"},{"key":"5985_CR87","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1089\/dna.2016.3488","volume":"35","author":"AR Massey","year":"2016","unstructured":"Massey AR, Beckham JD (2016) Alpha-synuclein, a novel viral restriction factor hiding in plain sight. DNA Cell Biol 35:643\u2013645. https:\/\/doi.org\/10.1089\/dna.2016.3488","journal-title":"DNA Cell Biol"},{"key":"5985_CR88","doi-asserted-by":"publisher","first-page":"721","DOI":"10.1007\/s00702-017-1726-7","volume":"124","author":"JJ Tomlinson","year":"2017","unstructured":"Tomlinson JJ, Shutinoski B, Dong L et al (2017) Holocranohistochemistry enables the visualization of \u03b1-synuclein expression in the murine olfactory system and discovery of its systemic anti-microbial effects. J Neural Transm 124:721\u2013738. https:\/\/doi.org\/10.1007\/s00702-017-1726-7","journal-title":"J Neural Transm"},{"key":"5985_CR89","doi-asserted-by":"publisher","first-page":"21416","DOI":"10.1074\/jbc.M110.103499","volume":"285","author":"KS Kim","year":"2010","unstructured":"Kim KS, Park J-Y, Jou I, Park SM (2010) Regulation of Weibel-Palade body exocytosis by \u03b1-Synuclein in endothelial cells. J Biol Chem 285:21416\u201321425. https:\/\/doi.org\/10.1074\/jbc.M110.103499","journal-title":"J Biol Chem"},{"key":"5985_CR90","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202101621r","author":"Y Takami","year":"2022","unstructured":"Takami Y, Wang C, Nakagami H et al (2022) Novel pathophysiological roles of \u03b1-synuclein in age\u2010related vascular endothelial dysfunction. FASEB J. https:\/\/doi.org\/10.1096\/fj.202101621r","journal-title":"FASEB J"},{"key":"5985_CR91","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3233\/JPD-140491","volume":"5","author":"HE Allen Reish","year":"2015","unstructured":"Allen Reish HE, Standaert DG (2015) Role of \u03b1-synuclein in inducing innate and adaptive immunity in Parkinson disease. J Parkinsons Dis 5:1\u201319. https:\/\/doi.org\/10.3233\/JPD-140491","journal-title":"J Parkinsons Dis"},{"key":"5985_CR92","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.562692","volume":"8","author":"V Grozdanov","year":"2020","unstructured":"Grozdanov V, Danzer KM (2020) Intracellular alpha-synuclein and immune cell function. Front Cell Dev Biol 8:562692. https:\/\/doi.org\/10.3389\/fcell.2020.562692","journal-title":"Front Cell Dev Biol"},{"key":"5985_CR93","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0071634","volume":"8","author":"SJ Gardai","year":"2013","unstructured":"Gardai SJ, Mao W, Sch\u00fcle B et al (2013) Elevated alpha-synuclein impairs innate immune cell function and provides a potential peripheral biomarker for parkinson\u2019s disease. PLoS One 8:e71634. https:\/\/doi.org\/10.1371\/journal.pone.0071634","journal-title":"PLoS One"},{"key":"5985_CR94","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1016\/j.neurobiolaging.2006.11.013","volume":"29","author":"A Klegeris","year":"2008","unstructured":"Klegeris A, Pelech S, Giasson BI et al (2008) \u0391-Synuclein activates stress signaling protein kinases in THP-1 cells and microglia. Neurobiol Aging 29:739\u2013752. https:\/\/doi.org\/10.1016\/j.neurobiolaging.2006.11.013","journal-title":"Neurobiol Aging"},{"key":"5985_CR95","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2018.00946","volume":"9","author":"AJ White","year":"2018","unstructured":"White AJ, Wijeyekoon RS, Scott KM et al (2018) The peripheral inflammatory response to Alpha-Synuclein and endotoxin in parkinson\u2019s disease. Front Neurol 9:946. https:\/\/doi.org\/10.3389\/fneur.2018.00946","journal-title":"Front Neurol"},{"key":"5985_CR96","doi-asserted-by":"publisher","first-page":"6386","DOI":"10.1007\/s00415-022-11258-w","volume":"269","author":"Y Su","year":"2022","unstructured":"Su Y, Shi C, Wang T et al (2022) Dysregulation of peripheral monocytes and pro-inflammation of alpha-synuclein in Parkinson\u2019s disease. J Neurol 269:6386\u20136394. https:\/\/doi.org\/10.1007\/s00415-022-11258-w","journal-title":"J Neurol"},{"key":"5985_CR97","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1016\/j.nbd.2005.08.002","volume":"21","author":"A Gerhard","year":"2006","unstructured":"Gerhard A, Pavese N, Hotton G et al (2006) In vivo imaging of microglial activation with [11 C](R)-PK11195 PET in idiopathic Parkinson\u2019s disease. Neurobiol Dis 21:404\u2013412. https:\/\/doi.org\/10.1016\/j.nbd.2005.08.002","journal-title":"Neurobiol Dis"},{"key":"5985_CR98","doi-asserted-by":"publisher","first-page":"2665","DOI":"10.1093\/brain\/awh625","volume":"128","author":"CF Orr","year":"2005","unstructured":"Orr CF, Rowe DB, Mizuno Y et al (2005) A possible role for humoral immunity in the pathogenesis of Parkinson\u2019s disease. Brain 128:2665\u20132674. https:\/\/doi.org\/10.1093\/brain\/awh625","journal-title":"Brain"},{"key":"5985_CR99","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24032477","volume":"24","author":"JS Deyell","year":"2023","unstructured":"Deyell JS, Sriparna M, Ying M, Mao X (2023) The interplay between \u03b1-synuclein and microglia in \u03b1-synucleinopathies. IJMS 24:2477. https:\/\/doi.org\/10.3390\/ijms24032477","journal-title":"IJMS"},{"key":"5985_CR100","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2018.00036","author":"MJ Benskey","year":"2018","unstructured":"Benskey MJ, Sellnow RC, Sandoval IM et al (2018) Silencing alpha synuclein in mature nigral neurons results in rapid neuroinflammation and subsequent toxicity. Front Mol Neurosci. https:\/\/doi.org\/10.3389\/fnmol.2018.00036","journal-title":"Front Mol Neurosci"},{"key":"5985_CR101","doi-asserted-by":"publisher","first-page":"702","DOI":"10.1016\/j.bbagen.2008.04.003","volume":"1790","author":"DR Richardson","year":"2009","unstructured":"Richardson DR, Kalinowski DS, Lau S et al (2009) Cancer cell iron metabolism and the development of potent iron chelators as anti-tumour agents. Biochimica et Biophysica Acta (BBA) 1790:702\u2013717. https:\/\/doi.org\/10.1016\/j.bbagen.2008.04.003","journal-title":"Biochimica et Biophysica Acta (BBA)"},{"key":"5985_CR102","doi-asserted-by":"publisher","first-page":"7938","DOI":"10.1021\/jp071439h","volume":"111","author":"L Hong","year":"2007","unstructured":"Hong L, Simon JD (2007) Current understanding of the binding sites, capacity, affinity, and biological significance of metals in melanin. J Phys Chem B 111:7938\u20137947. https:\/\/doi.org\/10.1021\/jp071439h","journal-title":"J Phys Chem B"},{"key":"5985_CR103","doi-asserted-by":"publisher","unstructured":"\u017b\u0105d\u0142o AC, Sarna T (2019) Interaction of iron ions with melanin. Acta Biochim Pol. https:\/\/doi.org\/10.18388\/abp.2019_2889","DOI":"10.18388\/abp.2019_2889"},{"key":"5985_CR104","doi-asserted-by":"publisher","first-page":"1423","DOI":"10.1016\/j.ejca.2003.11.035","volume":"40","author":"S Pavel","year":"2004","unstructured":"Pavel S, Van Nieuwpoort F, Van Der Meulen H et al (2004) Disturbed melanin synthesis and chronic oxidative stress in dysplastic naevi. Eur J Cancer 40:1423\u20131430. https:\/\/doi.org\/10.1016\/j.ejca.2003.11.035","journal-title":"Eur J Cancer"},{"key":"5985_CR105","doi-asserted-by":"publisher","first-page":"3657","DOI":"10.1021\/ic060014r","volume":"45","author":"LK Charkoudian","year":"2006","unstructured":"Charkoudian LK, Franz KJ (2006) Fe(III)-coordination properties of neuromelanin components: 5,6-dihydroxyindole and 5,6-dihydroxyindole-2-carboxylic acid. Inorg Chem 45:3657\u20133664. https:\/\/doi.org\/10.1021\/ic060014r","journal-title":"Inorg Chem"},{"key":"5985_CR106","doi-asserted-by":"publisher","first-page":"1856","DOI":"10.1016\/j.freeradbiomed.2010.09.010","volume":"49","author":"ZD Zhou","year":"2010","unstructured":"Zhou ZD, Lan YH, Tan EK, Lim TM (2010) Iron species-mediated dopamine oxidation, proteasome inhibition, and dopaminergic cell demise: implications for iron-related dopaminergic neuron degeneration. Free Radic Biol Med 49:1856\u20131871. https:\/\/doi.org\/10.1016\/j.freeradbiomed.2010.09.010","journal-title":"Free Radic Biol Med"},{"issue":"S1","key":"5985_CR107","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1111\/jnc.13425","volume":"139","author":"AA Belaidi","year":"2016","unstructured":"Belaidi AA, Bush AI (2016) Iron neurochemistry in Alzheimer\u2019s disease and Parkinson\u2019s disease: targets for therapeutics. J Neurochem 139(S1):179\u2013197. https:\/\/doi.org\/10.1111\/jnc.13425","journal-title":"J Neurochem"},{"key":"5985_CR108","doi-asserted-by":"publisher","first-page":"1953","DOI":"10.1093\/brain\/114.4.1953","volume":"114","author":"DT Dexter","year":"1991","unstructured":"Dexter DT, Carayon A, Javoy-Agid F (1991) Alterations in the levels of iron, ferritin and other trace metals in Parkinson\u2019s disease and other neurodegenerative diseases affecting the basal ganglia. Brain 114:1953\u20131975. https:\/\/doi.org\/10.1093\/brain\/114.4.1953","journal-title":"Brain"},{"key":"5985_CR109","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1016\/j.pneurobio.2015.09.012","volume":"155","author":"FA Zucca","year":"2017","unstructured":"Zucca FA, Segura-Aguilar J, Ferrari E et al (2017) Interactions of iron, dopamine and neuromelanin pathways in brain aging and Parkinson\u2019s disease. Prog Neurobiol 155:96\u2013119. https:\/\/doi.org\/10.1016\/j.pneurobio.2015.09.012","journal-title":"Prog Neurobiol"},{"key":"5985_CR110","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1080\/16078454.2022.2078041","volume":"27","author":"L Ling","year":"2022","unstructured":"Ling L, Wang F, Yu D (2022) Beyond neurodegenerative diseases: \u03b1-synuclein in erythropoiesis. Hematology 27:629\u2013635. https:\/\/doi.org\/10.1080\/16078454.2022.2078041","journal-title":"Hematology"},{"key":"5985_CR111","doi-asserted-by":"publisher","first-page":"10907","DOI":"10.1073\/pnas.0802437105","volume":"105","author":"CR Scherzer","year":"2008","unstructured":"Scherzer CR, Grass JA, Liao Z et al (2008) GATA transcription factors directly regulate the Parkinson\u2019s disease-linked gene \u03b1-synuclein. Proc Natl Acad Sci USA 105:10907\u201310912. https:\/\/doi.org\/10.1073\/pnas.0802437105","journal-title":"Proc Natl Acad Sci USA"},{"key":"5985_CR112","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0015814","volume":"6","author":"P Davies","year":"2011","unstructured":"Davies P, Moualla D, Brown DR (2011) Alpha-synuclein is a cellular ferrireductase. PLoS One 6:e15814. https:\/\/doi.org\/10.1371\/journal.pone.0015814","journal-title":"PLoS One"},{"key":"5985_CR113","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1016\/j.freeradbiomed.2019.06.024","volume":"141","author":"B Chen","year":"2019","unstructured":"Chen B, Wen X, Jiang H et al (2019) Interactions between iron and \u03b1-synuclein pathology in Parkinson\u2019s disease. Free Radic Biol Med 141:253\u2013260. https:\/\/doi.org\/10.1016\/j.freeradbiomed.2019.06.024","journal-title":"Free Radic Biol Med"},{"key":"5985_CR114","doi-asserted-by":"publisher","DOI":"10.3390\/biom15020214","volume":"15","author":"MA Khan","year":"2025","unstructured":"Khan MA (2025) \u0391-synuclein iron-responsive-element RNA and iron regulatory protein affinity is specifically reduced by iron in parkinson\u2019s disease. Biomolecules 15:214. https:\/\/doi.org\/10.3390\/biom15020214","journal-title":"Biomolecules"},{"key":"5985_CR115","doi-asserted-by":"publisher","first-page":"576","DOI":"10.1097\/WNR.0b013e328354a1f0","volume":"23","author":"F Febbraro","year":"2012","unstructured":"Febbraro F, Giorgi M, Caldarola S et al (2012) \u0391-synuclein expression is modulated at the translational level by iron. Neuroreport 23:576\u2013580. https:\/\/doi.org\/10.1097\/WNR.0b013e328354a1f0","journal-title":"Neuroreport"},{"key":"5985_CR116","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1038\/cdd.2009.116","volume":"17","author":"E Giaime","year":"2010","unstructured":"Giaime E, Sunyach C, Druon C et al (2010) Loss of function of DJ-1 triggered by parkinson\u2019s disease-associated mutation is due to proteolytic resistance to caspase-6. Cell Death Differ 17:158\u2013169. https:\/\/doi.org\/10.1038\/cdd.2009.116","journal-title":"Cell Death Differ"},{"key":"5985_CR117","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20133274","volume":"20","author":"F Limanaqi","year":"2019","unstructured":"Limanaqi F, Biagioni F, Busceti CL et al (2019) Phytochemicals bridging autophagy induction and alpha-synuclein degradation in parkinsonism. IJMS 20:3274. https:\/\/doi.org\/10.3390\/ijms20133274","journal-title":"IJMS"},{"key":"5985_CR118","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1007\/s12079-017-0402-x","volume":"11","author":"S Nandakumar","year":"2017","unstructured":"Nandakumar S, Vijayan B, Kishore A, Thekkuveettil A (2017) Autophagy enhancement is rendered ineffective in presence of \u03b1-synuclein in melanoma cells. J Cell Commun Signal 11:381\u2013394. https:\/\/doi.org\/10.1007\/s12079-017-0402-x","journal-title":"J Cell Commun Signal"},{"key":"5985_CR119","doi-asserted-by":"publisher","DOI":"10.1038\/s41531-023-00570-5","volume":"9","author":"FJ Hart De Ruyter","year":"2023","unstructured":"Hart De Ruyter FJ, Morrema THJ, Den Haan J et al (2023) \u0391-Synuclein pathology in post-mortem retina and optic nerve is specific for \u03b1-synucleinopathies. NPJ Parkinsons Dis 9:124. https:\/\/doi.org\/10.1038\/s41531-023-00570-5","journal-title":"NPJ Parkinsons Dis"},{"key":"5985_CR120","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21155563","volume":"21","author":"R Pinelli","year":"2020","unstructured":"Pinelli R, Biagioni F, Limanaqi F et al (2020) A re-appraisal of pathogenic mechanisms bridging wet and dry age-related macular degeneration leads to reconsider a role for phytochemicals. IJMS 21:5563. https:\/\/doi.org\/10.3390\/ijms21155563","journal-title":"IJMS"},{"key":"5985_CR121","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-12862-x","volume":"7","author":"S Baksi","year":"2017","unstructured":"Baksi S, Singh N (2017) \u0391-synuclein impairs ferritinophagy in the retinal pigment epithelium: implications for retinal iron dyshomeostasis in Parkinson\u2019s disease. Sci Rep 7:12843. https:\/\/doi.org\/10.1038\/s41598-017-12862-x","journal-title":"Sci Rep"},{"key":"5985_CR122","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1016\/j.neuroscience.2006.12.028","volume":"145","author":"S Yu","year":"2007","unstructured":"Yu S, Li X, Liu G et al (2007) Extensive nuclear localization of \u03b1-synuclein in normal rat brain neurons revealed by a novel monoclonal antibody. Neuroscience 145:539\u2013555. https:\/\/doi.org\/10.1016\/j.neuroscience.2006.12.028","journal-title":"Neuroscience"},{"key":"5985_CR123","doi-asserted-by":"publisher","first-page":"3107","DOI":"10.1093\/hmg\/ddaa183","volume":"29","author":"V Chen","year":"2020","unstructured":"Chen V, Moncalvo M, Tringali D et al (2020) The mechanistic role of alpha-synuclein in the nucleus: impaired nuclear function caused by familial parkinson\u2019s disease SNCA mutations. Hum Mol Genet 29:3107\u20133121. https:\/\/doi.org\/10.1093\/hmg\/ddaa183","journal-title":"Hum Mol Genet"},{"key":"5985_CR124","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1111\/phpp.12329","volume":"34","author":"A Sample","year":"2018","unstructured":"Sample A, He Y (2018) Mechanisms and prevention of UV-induced melanoma. Photoderm Photoimm Photomed 34:13\u201324. https:\/\/doi.org\/10.1111\/phpp.12329","journal-title":"Photoderm Photoimm Photomed"},{"key":"5985_CR125","doi-asserted-by":"publisher","first-page":"698","DOI":"10.1038\/labinvest.2016.155","volume":"97","author":"C-P Day","year":"2017","unstructured":"Day C-P, Marchalik R, Merlino G, Michael H (2017) Mouse models of UV-induced melanoma: genetics, pathology, and clinical relevance. Lab Invest 97:698\u2013705. https:\/\/doi.org\/10.1038\/labinvest.2016.155","journal-title":"Lab Invest"},{"key":"5985_CR126","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1039\/c1pp05131h","volume":"11","author":"SD Lamore","year":"2012","unstructured":"Lamore SD, Wondrak GT (2012) Autophagic-lysosomal dysregulation downstream of cathepsin B inactivation in human skin fibroblasts exposed to UVA. Photochem Photobiol Sci 11:163\u2013172. https:\/\/doi.org\/10.1039\/c1pp05131h","journal-title":"Photochem Photobiol Sci"},{"key":"5985_CR127","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1016\/j.brainresbull.2019.06.013","volume":"150","author":"R Maggio","year":"2019","unstructured":"Maggio R, Vaglini F, Rossi M et al (2019) Parkinson\u2019s disease and light: the bright and the dark sides. Brain Res Bull 150:290\u2013296. https:\/\/doi.org\/10.1016\/j.brainresbull.2019.06.013","journal-title":"Brain Res Bull"},{"key":"5985_CR128","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1016\/j.envres.2016.12.008","volume":"154","author":"A Kravietz","year":"2017","unstructured":"Kravietz A, Kab S, Wald L et al (2017) Association of UV radiation with Parkinson disease incidence: a nationwide French ecologic study. Environ Res 154:50\u201356. https:\/\/doi.org\/10.1016\/j.envres.2016.12.008","journal-title":"Environ Res"},{"key":"5985_CR129","doi-asserted-by":"publisher","DOI":"10.1038\/s41531-025-00928-x","volume":"11","author":"Q Wang","year":"2025","unstructured":"Wang Q, Duan Y, Xu Y et al (2025) Linking Parkinson\u2019s disease and melanoma: the impact of copper-driven Cuproptosis and related mechanisms. NPJ Parkinsons Dis 11:74. https:\/\/doi.org\/10.1038\/s41531-025-00928-x","journal-title":"NPJ Parkinsons Dis"},{"key":"5985_CR130","doi-asserted-by":"publisher","DOI":"10.1093\/sleep\/zsae229","volume":"48","author":"S Clemens","year":"2025","unstructured":"Clemens S, Zeczycki TN (2025) Challenging the paradigm of alpha-synuclein\u2019s role in disease: can low levels also be bad for you? Sleep 48:zsae229. https:\/\/doi.org\/10.1093\/sleep\/zsae229","journal-title":"Sleep"},{"key":"5985_CR131","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1212\/WNL.0000000000006926","volume":"92","author":"AJ Espay","year":"2019","unstructured":"Espay AJ, Vizcarra JA, Marsili L et al (2019) Revisiting protein aggregation as pathogenic in sporadic Parkinson and Alzheimer diseases. Neurology 92:329\u2013337. https:\/\/doi.org\/10.1212\/WNL.0000000000006926","journal-title":"Neurology"}],"container-title":["Cellular and Molecular Life Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00018-025-05985-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00018-025-05985-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00018-025-05985-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T08:11:33Z","timestamp":1786435893000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00018-025-05985-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,29]]},"references-count":131,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["5985"],"URL":"https:\/\/doi.org\/10.1007\/s00018-025-05985-2","relation":{},"ISSN":["1420-9071"],"issn-type":[{"value":"1420-9071","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,29]]},"assertion":[{"value":"25 June 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 October 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 November 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 December 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","label":"Conflict of interest","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"7"}}