Knocking out alpha-synuclein in melanoma cells downregulates L1CAM and decreases motility

Abstract

The Parkinsons disease (PD) associated protein, alpha-synuclein (-syn/SNCA), is highly expressed in aggressive melanomas, which raises the possibility that -syn has a pro-survival function in melanoma. Herein, we asked whether -syn modulates the expression of the pro-oncogenic adhesion molecules L1CAM and N-cadherin. We used two human melanoma cell lines (SK-MEL-28, SK-MEL-29), SNCA-knockout (KO) clones, and two human SH-SY5Y neuroblastoma cell lines. In the melanoma lines, loss of -syn expression resulted in significant decreases in the expression of L1CAM and N-cadherin and concomitant significant decreases in motility. On average, there was a 75% reduction in motility in the four SNCA-KOs tested compared to control cells. Strikingly, comparing neuroblastoma SH-SY5Y cells that have no detectable -syn to SH-SY5Y cells that stably express -syn (SH/+S), we found that expressing -syn increased L1CAM and single-cell motility by 54% and 597%, respectively. The reduction in L1CAM level in SNCA-KO clones was not due to a transcriptional effect, rather we found that L1CAM is more efficiently degraded in the lysosome in SNCA-KO clones than in control cells. We propose that -syn is pro-survival to melanoma (and possibly neuroblastoma) because it promotes the intracellular trafficking of L1CAM.