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Whether this indicates melanoma progression or constitutes a protective response remains unclear. We hereby investigated the molecular mechanisms through which \u03b1\u2010synuclein and DJ\u20101 interact, suggesting novel biomarkers and targets in melanoma.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The Cancer Genome Atlas (TCGA) expression profiles derived from UCSC Xena were used to obtain \u03b1\u2010synuclein and DJ\u20101 expression and correlated with survival in skin cutaneous melanoma (SKCM). Immunohistochemistry determined the expression in metastatic melanoma lymph nodes. Protein\u2013protein interactions (PPIs) and molecular docking assessed protein binding and affinity with chemotherapeutic drugs. Further validation was performed using in\u00a0vitro cellular models and ELISA immunoassays.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>\u03b1\u2010synuclein and DJ\u20101 were upregulated in primary and metastatic SKCM. Aggregated \u03b1\u2010synuclein was selectively detected in metastatic melanoma lymph nodes. \u03b1\u2010synuclein overexpression in SK\u2010MEL\u201028 cells induced the expression of DJ\u20101, supporting PPI and a positive correlation in melanoma patients. Molecular docking revealed a stable protein complex, with differential binding to chemotherapy drugs such as temozolomide, dacarbazine, and doxorubicin. Parallel reduction of both proteins in temozolomide\u2010treated SK\u2010MEL\u201028 spheroids suggests drug binding may affect protein interaction and\/or stability.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>\u03b1\u2010synuclein, together with DJ\u20101, may play a role in melanoma progression and chemosensitivity, constituting novel targets for therapeutic intervention, and possible biomarkers for melanoma.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cam4.6900","type":"journal-article","created":{"date-parts":[[2024,1,8]],"date-time":"2024-01-08T13:29:50Z","timestamp":1704720590000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Uncovering potential diagnostic and pathophysiological roles of \u03b1\u2010synuclein and <scp>DJ<\/scp>\u20101 in melanoma"],"prefix":"10.1002","volume":"13","author":[{"given":"Agathe","family":"Quesnel","sequence":"first","affiliation":[{"name":"School of Health &amp; 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