Physiological phenotype and vulnerability in Parkinson's disease

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Abstract

This review 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 (PD) and aging. A cornerstone of this hypothesis is that the maintenance of ionic gradients underlying excitability can pose a significant energetic burden for neurons, particularly those that have sustained residence times at depolarized membrane potentials, broad action potentials, prominent Ca2+ entry, and modest intrinsic Ca2+ buffering capacity. 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 (ROS) that have widely been postulated to contribute to cellular aging and PD. Many of the genetic mutations and toxins associated with PD 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 feasible. © 2012 Cold Spring Harbor Laboratory Press; all rights reserved.

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APA

James Surmeier, D., Guzman, J. N., Sanchez, J., & Schumacker, P. T. (2012). Physiological phenotype and vulnerability in Parkinson’s disease. Cold Spring Harbor Perspectives in Medicine. Cold Spring Harbor Laboratory Press. https://doi.org/10.1101/cshperspect.a009290

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