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The Role of  -Synuclein in Both Neuroprotection and Neurodegeneration
aDepartment of Pediatrics, Georgetown University, Washington, District of Columbia 20007, USA bInstitut de Neurobiologie Alfred FESSARD, CNRS, 91198 Gif-sur-Yvette Cedex, France
Address for correspondence: Dr. Anita Sidhu, Head, Laboratory of Molecular Neurochemistry, The Research Building, Room W222, 3970 Reservoir Road, NW, Washington, D.C. 20007. Voice: 202-687-0282; fax: 202-687-0279. sidhua{at}georgetown.edu
Although
 -synuclein is a central player in the pathophysiology of the dopaminergic neurodegeneration that occurs in Parkinson's disease (PD), emerging results suggest that the fundamental property of the wild-type form of this protein may be one of neuroprotection, as it can inhibit apoptosis in response to various pro-apoptotic stimuli. Such properties may be lost by its familial PD-linked mutations upon alterations in its expression levels or clearance (overexpression of the gene, reduced protein degradation) or following exposure to certain neurotoxins. Moreover, converging observations suggest that a primary function for -synuclein in dopaminergic neurons may be the regulation of dopamine content and tone at the synapse. In this paper, we review how, indeed, -synuclein regulates both the synthesis of dopamine, its storage into vesicles, its release in the synapse, and its re-uptake into the dopaminergic neurons. We also show how disruption of these events, and of the neuroprotective effects of -synuclein, can initiate the observed neurotoxicity of -synuclein in dopaminergic neurons and the genesis of the degenerative processes associated with PD.
Key Words: dopamine transporter • -synuclein • Parkinson's disease • MPTP • neurodegeneration • neuroprotection • apoptosisThis article has been cited by other articles:
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