Alpha-Synuclein Inhibits the Secretion of Extracellular Vesicles through Disruptions in YKT6 Lipidation

Parkinson's disease is characterized by the presence of alpha-synuclein (α-syn) primarily containing Lewy bodies in neurons. Despite decades of extensive research on α-syn accumulation, its molecular mechanisms have remained largely unexplored. Recent studies by us and others have suggested that extracellular vesicles (EVs), especially exosomes, can mediate the release of α-syn from cells and inhibiting this pathway could result in increased intracellular α-syn levels. In this study, we have discovered that elevated levels of α-syn themselves lead to reduced α-syn -containing EVs in α-syn-inducible H4 cells and induced pluripotent stem cell-derived dopaminergic (DA) neurons from both sexes. Our investigations have revealed that the impairment in EV secretion is not due to their generation but rather a consequence of changes in a soluble <i>N</i>-ethylmaleimide-sensitive factor attachment protein receptor protein, YKT6. Specifically, as α-syn levels increase, membrane-associated YKT6 is reduced. Pharmacological inhibition of farnesylation using FTI has led to decreased EV secretion and subsequent elevated levels of α-syn. In summary, our findings suggest that increased levels of α-syn impair YKT6-mediated EV secretion, establishing a detrimental cycle of intracellular α-syn accumulation in human DA neurons.