Mutations in α‐synuclein, a protein highly enriched in presynaptic terminals, have been implicated in the expression of familial forms of Parkinson’s disease (PD) whereas native α‐synuclein is a major component of intraneuronal inclusion bodies characteristic of PD and other neurodegenerative disorders. Although overexpression of human α‐synuclein induces dopaminergic nerve terminal degeneration, the molecular mechanism by which α‐synuclein contributes to the degeneration of these pathways remains enigmatic. We report here that α‐synuclein complexes with the presynaptic human dopamine transporter (hDAT) in both neurons and cotransfected cells through the direct binding of the non‐Aβ amyloid component of α‐synuclein to the carboxyl‐terminal tail of the hDAT. α‐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.—Lee, F. J. S., Liu, F., Pristupa, Z. B., Niznik, H. B. Direct binding and functional coupling of α‐synuclein to the dopamine transporter accelerate dopamine‐induced apoptosis. FASEB J. 15, 916–926 (2001)