Can Interactions Between α-Synuclein, Dopamine and Calcium Explain Selective Neurodegeneration in Parkinson's Disease?

Abstract

Several lines of evidence place alpha-synuclein (aSyn) at the center of Parkinson's disease (PD) etiology, but it is still unclear why overexpression or mutated forms of this protein affect some neuronal populations more than others. Susceptible neuronal populations in PD, dopaminergic neurons of the substantia nigra pars compacta (SNpc) and the locus coeruleus (LC), are distinguished by relatively high cytoplasmic concentrations of dopamine and calcium ions. Here we review the evidence for the multi-hit hypothesis of neurodegeneration, including recent papers that demonstrate synergistic interactions between aSyn, calcium ions and dopamine that may lead to imbalanced protein turnover and selective susceptibility of these neurons. We conclude that decreasing the levels of any one of these toxicity mediators can be beneficial for the survival of SNpc and LC neurons, providing multiple opportunities for targeted drug interventions aimed at modifying the course of PD.

Keywords: Parkinson's disease; calcium; dopamine; locus coeruleus; multiple hits; substantia nigra pars compacta; α-Synuclein.

Figure 1

aSyn sequence map. An annotated structure of human micelle-bound aSyn solved by solution NMR (PDB 1XQ8) (Ulmer et al., 2005) and corresponding sequence have been color coded to highlight the lipid binding N-terminal domain and associated KTK motifs (cyan), common familial PD mutations (green), acidic residues in the C-terminal Ca²⁺-binding EF-hand-like motif (pink), and the dopamine-binding residues (yellow).

Figure 2

Model of cell-selective PD pathogenesis. (1) A physiological function of aSyn may be to bind synaptic vesicles in a reversible manner to inhibit exocytosis. (2) aSyn is degraded by CMA following LAMP-2A-mediated transport into the lysosomes. (3) In SN and LC neurons, high Ca²⁺ levels upregulate TH and AADC, leading to increased DA concentrations and (4) associated oxyradical stress, which induces various cell defense mechanisms, including (5) CMA. (6) DA-modified aSyn (7) blocks LAMP-2A-mediated uptake of CMA substrates, including aSyn itself. (8) aSyn may oligomerize to toxic protofibrils, which can (9) bind to and (10) permeabilize synaptic vesicles, leading to further increase in cytosolic DA. (11) DA stabilizes aSyn protofibrils, inhibiting the formation of larger polymers of aSyn (12). Overall, the presence of such interactions where DA and aSyn act as independent stressors that converge to produce neurotoxicity may explain why catecholaminergic neurons with Ca⁺² channel- mediated pacemaking are more prone to produce neuromelanin and Lewy bodies, and are particularly vulnerable in PD and parkinsonian animal models. Only a few aSyn-DA-Ca²⁺ interactions discussed in the text are shown.