The secreted oligomeric form of α-synuclein affects multiple steps of membrane trafficking.

α-Synuclein (α-syn) can be secreted from neurons into the extracellular space, affecting the homeostasis of neighboring cells, but the pathophysiology of secreted α-syn remains largely unknown. We found that when exogenously applied to COS-7 cells, α-syn secreted from differentiated SH-SY5Y cells was taken up by dynamin-dependent endocytosis. Upon internalization, α-syn significantly increased the rate of transferrin receptor (TfR) internalization and recycling, and subsequently the surface levels of TfR. The effects are attributable to the oligomeric form, but not monomeric or fibrillar form, of extracellular α-syn. Together, multiple alterations in membrane trafficking by secreted oligomeric α-syn may contribute to the early stages of pathogenesis in Parkinson's disease.