Release and uptake of pathologic alpha-synuclein

Parkinson's disease (PD) is a chronic progressive neurodegenerative disease, which is characterized by severe loss of dopaminergic neurons and formation of Lewy bodies, which are rich in aggregated alpha-synuclein (α-syn). Two decades of intensive research have compiled a massive body of evidence that aggregation of α-syn is a critical process in PD and other synucleinopathies. The dissemination of Lewy body pathology throughout the central nervous system strongly suggests a cell-to-cell transmission of α-syn. Although in vitro and in vivo evidence has convincingly demonstrated that aggregation-prone α-syn can spread from cell to cell, the exact mechanisms and the role for the disease pathology remain elusive. Except for cases of direct contact, the transmission of α-syn from cell to cell requires that α-syn is released to the extracellular space and taken up by recipient cells. Furthermore, internalized α-syn needs to gain access to the cytoplasm and/or target organelles of the recipient cell. Here, we review the current state of knowledge about release and uptake of α-syn and discuss the key questions that remain unanswered.