Alpha-synuclein modulates the positioning of endolysosomes in melanoma cells

The Parkinson's disease-associated protein, alpha-synuclein (α-syn; SNCA) is suspected of promoting melanoma progression. We recently knocked out SNCA in the human cutaneous melanoma cell line SK-MEL-28 to try to deduce the role of α-syn in melanoma progression. Compared to control cells, the SK-MEL-28 SNCA-knockout (KO) cells have significantly inhibited growth, invasion, and migration, and the levels of the neural adhesion protein L1CAM and the transferrin receptor (TFR1) are significantly reduced. In this study, using transmission electron microscopy and immunofluorescence we show that SK-MEL-28 SNCA-KO cells relative to control cells exhibit an (i) increased density of endolysosomes; (ii) increased perinuclear positioning of large (> 800 nm) endolysosomes; and (iii) decreased levels of the tetraspanins CD9 and CD81. Based on these results, we infer that α-syn disrupts the balance between anterograde and retrograde traffic; thus, we propose that α-syn is an accessory factor that that positively modulates the anterograde transport of endolysosomes and that loss of α-syn expression results events (i)-(iii). We infer that low levels of L1CAM and CD81 (and other membrane proteins) are likely the underlying reason for the significantly reduced invasiveness and migratory properties of SK-MEL-28 SNCA-KO cells.