Alpha- and Gamma-Synuclein Proteins Define Complementary Metabolic and Invasive Programs in Melanoma Development, Progression, and Prognosis

Abstract Melanoma, a highly aggressive skin cancer, remains a major clinical challenge due to its metastatic capacity and resistance to therapy. Synuclein proteins — alpha-synuclein (αS) and gamma-synuclein (γS), traditionally studied in neurodegeneration — are increasingly recognized as contributors to melanoma progression, yet whether they define distinct tumor cell states or act through shared mechanisms remains unclear. Here, we show that SNCA and SNCG are robustly anti-correlated across independent transcriptomic and proteomic cohorts and at single-cell resolution, marking two complementary malignant cell states. Both synucleins support melanoma proliferation, migration, and invasion, and are internalized by melanoma cells in a prion-like manner that enhances tumor growth in vitro and in vivo. Functionally, however, αS and γS diverge along distinct axes. αS is transcriptionally coupled to a MITF-linked mitochondrial program and functionally sensitizes complex I: its silencing improves mitochondrial bioenergetics and blunts the response to a second respiratory challenge, while exogenous fibrils impair it, alongside a corresponding shift in pigmentation. γS instead sustains an integrin-FAK-Rac1-MAPK signaling axis and β-catenin regulation that drives invasive behavior; its silencing reduces MAPK output and confers cross-resistance to three mechanistically distinct therapeutic agents — cisplatin, vemurafenib, and paclitaxel. These opposing programs converge on a shared differentiation axis: SNCG-high cells define a dedifferentiated, MITF-low, invasive malignant subpopulation that is independently associated with shorter progression-free interval in stage IIC melanoma. Collectively, these findings establish αS and γS as functionally distinct, mechanistically convergent regulators of a metabolic-versus-invasive cell-state dichotomy in melanoma, nominate SNCG as a candidate prognostic biomarker, and identify complex I sensitization and FAK/MAPK signaling as candidate therapeutic vulnerabilities.