Physiological Phenotype and Vulnerability in Parkinson's Disease

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 Ca 2þ entry, and modest intrinsic Ca 2þ 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 atrisk phenotype is created by Ca 2þ 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.

From Intrinsic Firing Properties to Selective Neuronal Vulnerability in Neurodegenerative Diseases

“…Several genetic and pharmacological animal models of PD target mitochondrial function, leading to elevated cytosolic calcium levels and reduced excitability of vulnerable SNc DA neurons Surmeier et al, 2010;Guzman et al, 2010;Surmeier et al, 2012;Masi et al, 2013;Hirsch et al, 2013). The resulting silencing of vulnerable neurons involves both burst and pacemaking firing and precedes neuronal degeneration (Good et al, 2011;Michel et al, 2013).…”

Calcium CaV1 Channel Subtype mRNA Expression in Parkinson’s Disease Examined by In Situ Hybridization

“…The resulting metabolic burden that use of calcium for creation of electrochemical gradients (as opposed to sodium or potassium) places upon neurons has been posited to explain the susceptibility of brainstem (medulla, pons and midbrain) neurons to the detrimental effects of mitochondrial dysfunction and oxidative stress (whether innate or due to an as yet unidentified environmental toxin) when compared to neurons that do not rely on Ca V 1.3 for autonomous firing (e.g. cortical neurons), which are less vulnerable to neurodegeneration in Parkinson's disease (Surmeier et al 2012).…”

The pathology roadmap in Parkinson disease

“…An extended discussion of this hypothesis has recently been published. 73 PD is a disease of neurons, not of the liver, kidney or heart. An implication of this fact is that one or more of the features distinguishing neurons from these other cell types must contribute in a seminal way to pathogenesis.…”