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.
Highlights
Departments of Psychiatry and Neurology, New York State Psychiatric Institute, Columbia University Medical Center, New York, NY, United States
We conclude that decreasing the levels of any one of these toxicity mediators can be beneficial for the survival of substantia nigra pars compacta (SNpc) and locus coeruleus (LC) neurons, providing multiple opportunities for targeted drug interventions aimed at modifying the course of Parkinson’s disease (PD)
These interactions demonstrate the precarious nature of SNpc and LC neuron health as, if one aspect of the homeostatic processes goes awry, the feedback loops activate and neurotoxicity ensues
Summary
Parkinson’s disease (PD), the second most common neurodegenerative disorder (De Lau and Breteler, 2006), is marked by slowness (bradykinesia), resting tremor, muscular rigidity, and postural instability (Lang and Lozano, 1998). After further breeding to reintroduce the wild-type aSyn gene, the resulting VMAT2-LO mice showed signs of PD-like progressive neurodegeneration, including L-DOPA-responsive motor deficits, oxidative stress and protein damage, decreased DA, DAT, and TH levels in the striatum, and pathological accumulations of aSyn and a reduced number of DA neurons in the SNpc (Caudle et al, 2007; Taylor et al, 2011). L-DOPA treatment produces higher concentration of cytosolic catecholamines in cultured SNpc (Mosharov et al, 2009) and LC (unpublished data) compared to VTA neurons, which translated into higher susceptibility of these neurons to LDOPA-induced degeneration The difference between these cell types was normalized by pharmacological or genetic blockade of the LTCCs, confirming their role in selective PD-like neurodegeneration. Underlying species-specific differences may explain the difficulties of creating an appropriate mouse model of PD
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