α-Synuclein interferes with the ESCRT-III complex contributing to the pathogenesis of Lewy body disease

alpha-Synuclein (alpha-syn) has been implicated in neurological disorders with parkinsonism, including Parkinson's disease and Dementia with Lewy body. Recent studies have shown alpha-syn oligomers released from neurons can propagate from cell-to-cell in a prion-like fashion exacerbating neurodegeneration. In this study, we examined the role of the endosomal sorting complex required for transport (ESCRT) pathway on the propagation of alpha-syn. alpha-syn, which is transported via the ESCRT pathway through multivesicular bodies for degradation, can also target the degradation of the ESCRT protein-charged multivesicular body protein (CHMP2B), thus generating a roadblock of endocytosed alpha-syn. Disruption of the ESCRT transport system also resulted in increased exocytosis of alpha-syn thus potentially increasing cell-to-cell propagation of synuclein. Conversely, delivery of a lentiviral vector overexpressing CHMP2B rescued the neurodegeneration in alpha-syn transgenic mice. Better understanding of the mechanisms of intracellular trafficking of alpha-syn might be important for understanding the pathogenesis and developing new treatments for synucleinopathies.