Direct binding and functional coupling of α-synuclein to the dopamine transporters accelerate dopamine-induced apoptosis
Lee, F.J.S.; Liu, F.; Pristupa, Z.B.; Niznik, H.B.
FASEB Journal 15(6): 916-926
2018
ISSN/ISBN: 0892-6638 PMID: 29461115 Document Number: 696795
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.