Increased cellular concentration of alpha-synuclein (alpha-syn) predisposes it to misfolding and aggregation that in turn impair the degradation pathways. This poses a limitation to the use of overexpression models for studies on alpha-syn clearance by autophagy, which is widely investigated for its therapeutic potential. This limitation can be overcome with the use of endogenous models. In this study, SK-MEL-28, a melanoma cell model with endogenous alpha-syn expression, was employed to study alpha-syn clearance through autophagy. We demonstrated the dual localization of alpha-syn to nucleus and cytoplasm that varied in response to changes in cellular environment. Autophagy inhibition and exposure to dopamine favored cytoplasmic localization of alpha-syn, while autophagy induction favored increased localization to the nucleus. The inhibitory effect of dopamine on autophagy was heightened in presence of alpha-syn. Additionally, because alpha-syn had a regulatory effect on autophagy, cells showed an increased resistance to autophagy induction in presence of alpha-syn. This resistance prevented effective induction of autophagy even under conditions of prolonged autophagy inhibition. These results highlight alternate physiological roles of alpha-syn, particularly in non-neuronal cells. Because autophagy enhancement could reverse neither the increase in alpha-syn levels nor the autophagy inhibition, there arises a need to evaluate the efficacy of autophagy-based therapeutic strategies.