Calcium influx, free radicals, and aging: A metabolic burden linked to neuronal loss in Parkinson’s disease

Research output: Chapter in Book/Report/Conference proceedingChapter

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 significant 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.

Original languageEnglish (US)
Title of host publicationParkinson's Disease, Second Edition
PublisherCRC Press
Pages1097-1104
Number of pages8
ISBN (Electronic)9781439807156
ISBN (Print)9781439807149
DOIs
StatePublished - Jan 1 2012

ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)

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