The role of alpha-synuclein in both neuroprotection and neurodegeneration.
Although alpha-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 alpha-synuclein in dopaminergic neurons may be the regulation of dopamine content and tone at the synapse. In this paper, we review how, indeed, alpha-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 alpha-synuclein, can initiate the observed neurotoxicity of alpha-synuclein in dopaminergic neurons and the genesis of the degenerative processes associated with PD.
Sidhu
Anita
A
Department of Pediatrics, Georgetown University, Washington, DC 20007, USA. sidhua@georgetown.edu
Wersinger
Christophe
C
Moussa
Charbel E-H
CE
Vernier
Philippe
P
D000818:Animals; D004298:Dopamine / Q000378:metabolism; D006801:Humans; D008959:Models, Neurological; D009410:Nerve Degeneration / Q000378:metabolism / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051844:alpha-Synuclein / Q000627:therapeutic use*
D018696:Neuroprotective Agents; D051844:alpha-Synuclein; D004298:Dopamine