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-synuclein to the dopamine transporters accelerate dopamine-induced apoptosis
1
,,,
,
* Department of Pharmacology,
Psychiatry and
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 
-synuclein, a protein highly enriched in presynaptic
terminals, have been implicated in the expression of familial forms of
Parkinson’s disease (PD) whereas native -synuclein is a major
component of intraneuronal inclusion bodies characteristic of PD and
other neurodegenerative disorders. Although overexpression of human
-synuclein induces dopaminergic nerve terminal degeneration, the
molecular mechanism by which -synuclein contributes to the
degeneration of these pathways remains enigmatic. We report here that
-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 -synuclein to the
carboxyl-terminal tail of the hDAT. -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
-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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