Calcium, metabolic stress and neuronal vulnerability in Parkinson’s disease: Breaking old bonds to halt the disease
James Surmeier, PhD
Professor of Physiology, Northwestern UniversityHosts: Jun Ding & Xinnan Wang
This talk will focus on the principles underlying the hypothesis that neuronal physiological phenotype – how a neuron generates and regulates action potentials – makes a significant contribution to its vulnerability in Parkinson’s disease and aging. A cornerstone of this hypothesis is that the maintenance of ionic gradients underlying excitability can pose a significant energetic burden for some neurons, particularly those that have sustained Ca2+ entry. This energetic burden is shouldered in neurons primarily by mitochondria, the sites of cellular respiration. Mitochondrial respiration increases the production of damaging superoxide and other reactive oxygen species that have widely been postulated to contribute to cellular aging and Parkinson’s disease. Many of the genetic mutations and toxins associated with Parkinson’s disease compromise mitochondrial function, providing a mechanistic linkage between known risk factors and cellular physiology that could explain the pattern of pathology in PD. Because much of the mitochondrial burden created by this at-risk phenotype is created by Ca2+ entry through L-type voltage-dependent channels for which there are antagonists approved for human use, a neuroprotective strategy to reduce this burden is being tested in a large scale, Phase III clinical trial in the U.S.