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(The FASEB Journal. 2001;15:916-926.)
© 2001 FASEB

Direct binding and functional coupling of {alpha}-synuclein to the dopamine transporters accelerate dopamine-induced apoptosis

FRANK J. S. LEE*,§1, FANG LIU{dagger},§, ZDENEK B. PRISTUPA{dagger},§ and HYMAN B. NIZNIK*,{dagger},{ddagger},§

* Department of Pharmacology,
{dagger} Psychiatry and
{ddagger} Institute of Medical Sciences, University of Toronto, Toronto, Ontario M5S 1A8, Canada; and
§ Lab of Molecular Neurobiology, Centre for Addiction and Mental Health, Toronto, Ontario, M5T 1R8, Canada

1Correspondence: Laboratory of Molecular Neurobiology, Centre for Addiction and Mental Health, 250 College St., Toronto, Ontario, M5T 1R8 Canada. E-mail: f.lee{at}utoronto.ca

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 {alpha}-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-Aß 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.—Lee, F. J. S., Liu, F., Pristupa, Z. B., Niznik, H. B. Direct binding and functional coupling of {alpha}-synuclein to the dopamine transporter accelerate dopamine-induced apoptosis.


Key Words: DA uptake • cell death • coimmunoprecipitation • GST fusion proteins • Parkinson’s disease




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