Direct binding and functional coupling of α-synuclein to the dopamine transporters accelerate dopamine-induced apoptosis

Mutations in alpha -synuclein, a protein highly enriched in presynaptic terminals, have been implicated in the expression of familial forms of Parkinson's disease (PD) whereas native alpha -synuclein is a major component of intraneuronal inclusion bodies characteristic of PD and other neurodegenerative disorders. Although overexpression of human a-synuclein induces dopaminergic nerve terminal degeneration, the molecular mechanism by which alpha -synuclein contributes to the degeneration of these pathways remains enigmatic, We report here that alpha -synuclein complexes with the presynaptic human dopamine transporter (hDAT) in both neurons and cotransfected cells through the direct binding of the non-A beta amyloid component of alpha -synuclein to the carboxyl-terminal tail of the hDAT, alpha -Synuclein-hDAT complex formation facilitates the membrane clustering of the DAT, thereby accelerating cellular dopamine uptake and dopamine-induced cellular apoptosis, Since the selective vulnerability of dopaminergic neurons in PD has been ascribed in part to oxidative stress as a result of the cellular overaccumulation of dopamine or dopamine-like molecules by the presynaptic DAT, these data provide mechanistic insight into the mode by which the activity of these two proteins may give rise to this process.