ABSTRACT
Aside from all the known neuropathology that has been described in PD, the mechanisms responsible for the preferential loss of DA neurons in PD have been debated for decades. A widely held theory implicates oxidation of cytosolic DA (and its metabolites) leading to the production of cytotoxic free radicals [7,8]. However, there are reasons to doubt this type of cellular stress alone is responsible for the loss of DA neurons in PD. For example, there is considerable regional variability in the vulnerability of DA neurons in PD, with some being devoid of pathological markers [9-13]. Moreover, levodopa administration (which relieves symptoms by elevating DA levels in PD patients) does not appear to accelerate disease progression [14], suggesting that DA is not a signicant source of reactive oxidative stress, at least in the short term. Sulzer et al. have recently reported
that calcium (Ca2+) entry through L-type channels stimulates DA metabolism in substantia nigra pars compacta (SNc) DA neurons, pushing cytosolic DA concentrations into a toxic range with levodopa loading [15]. For this mechanism to be relevant to selective vulnerability, one would have to posit that modest elevations in cytosolic DA over decades lead to an accumulation of cellular defects that ultimately produce cell death. Although plausible, the hypothesis is not readily testable. It does suggest that treating patients in the early stages of the disease with direct acting agonists, rather than levodopa, should lead to a slower progression of the disease. That said, the frank death or phenotypic decline of a variety of non-dopaminergic neurons in PD argues that DA itself is not likely to be the principal culprit in the disease.
