α-Synuclein and dopamine at the crossroads of Parkinson's disease

Abstract

α-Synuclein is central to the Lewy body neuropathology of Parkinson's disease (PD), a devastating neurodegenerative disorder characterized by numerous motor and non-motor manifestations. The cardinal motor symptoms are linked to death of dopaminergic neurons in the nigrostriatal pathway. Here we ask why these neurons are preferentially susceptible to neurodegeneration in PD and how α-synuclein is involved. To address these questions we bring together recent findings from genome-wide association studies, which reveal the involvement of α-synuclein gene variants in sporadic PD, with recent studies highlighting important roles for α-synuclein in synaptic transmission and dopaminergic neuron physiology. These latest advances add to our understanding of PD etiology and provide a central link between the genetic findings and neurodegeneration observed in sporadic PD.

Copyright © 2010 Elsevier Ltd. All rights reserved.

Figures

Figure I

Schematic representation of human α-synuclein depicting: (a) SNCA gene structure, (b) mRNA, and (c) protein domains.

Figure 1

Possible SNCA-associated disease mechanisms. (a) Recent genetic studies have identified common variants at the SNCA locus which are associated with sporadic PD [16,17,20]. The three single nucleotide polymorphisms (SNPs) that were found to be most highly associated with PD (rs2736990, rs3857059 and rs11931074) are indicated by green arrows. Such variants could affect α-synuclein function and contribute to PD etiology by altering levels of gene transcription, altering mRNA stability (via altered miRNA binding) or by altering the generation of alternative splice isoforms. Some of the 3′ SNPs identified are in linkage disequilibrium (LD) with the REP1 dinucleotide repeat in the promoter region (indicated in red), previously found to regulate SNCA expression [25,26]. (b) Alternative splicing of exons 3 and 5 generates four SNCA isoforms of different lengths, one of which (SNCA112; exon 3+5−) has been implicated in Lewy body formation and neurotoxicity [31].

Figure 2

Effects of α-synuclein on dopamine homeostasis in the presynaptic terminal. Dopamine is synthesized in the cytoplasm by the action of tyrosine hydroxylase (TH) and amino acid decarboxylase (AADC). (i)α-Synuclein has been shown to regulate the activity of these enzymes [35,36,43]. (ii) Once synthesized, dopamine is immediately sequestered into vesicles by the vesicular monoamine transporter 2 (VMAT2). Several lines of evidence suggest that α-synuclein is involved in regulating synaptic vesicle function and dopamine release into the synaptic cleft [–53]. (iii) Dopaminergic signaling at the synapse is terminated by the reuptake of dopamine via the dopamine transporter (DAT), with co-transport of two Na+ and one Cl− ions. Studies in cell culture systems have shown that α-synuclein is necessary for the trafficking of DAT to the cell surface [–64].

Figure 3

Schematic model of α-synuclein’s proposed roles in regulating presynaptic vesicle cycling in situations of different α-synuclein levels. (a) When α-synuclein levels are reduced the availability of vesicles in the reserve pool is decreased [49,50] and more vesicles are readily available to be released [52], and this can lead to an increase in dopamine release. (b) Under normal conditions α-synuclein is thought to play a physiological role in regulating vesicle availability in the different pools and vesicle docking and fusion. (c) By contrast, elevated α-synuclein levels or mutated E46K or A53T α-synuclein lead to a reduction in dopamine release [56,57] possibly by affecting a late step in exocytosis [57] or by decreasing vesicle availability in the recycling pool due to impaired vesicle endocytosis [51].

Figure 4

A schematic working model illustrating various proposed cellular mechanisms for how preferential neurodegeneration of substantia nigra pars compacta (SNc) dopaminergic neurons could take place. Neurons in the SNc display characteristics which make them highly susceptible to cell death, for example a higher dopamine transporter (DAT)/vesicular monoamine transporter 2 (VMAT2) ratio [82,83] and the use of CaV1.3 calcium (Ca2+) channels for autonomous pacemaking [78]. Subtle increases in Ca2+ levels in the cytoplasm activate dopamine (DA) synthesis [90]. Impairment of vesicle docking and recycling due to α-synuclein dysfunction could prevent incorporation of newly synthesized and newly taken up DA into vesicles. This could lead to an increase in cytosolic DA concentration (DAcyt), which causes increased generation of toxic reactive species and ultimately contributes to dopaminergic neurodegeneration. Thus, the combined action of α-synuclein dysfunction and increased dopamine in the cytosol of SNc neurons could drive cell death in Parkinson’s disease (PD).