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. 2011 Dec 15;198:221-31.
doi: 10.1016/j.neuroscience.2011.08.045. Epub 2011 Aug 25.

The Role of Calcium and Mitochondrial Oxidant Stress in the Loss of Substantia Nigra Pars Compacta Dopaminergic Neurons in Parkinson's Disease

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The Role of Calcium and Mitochondrial Oxidant Stress in the Loss of Substantia Nigra Pars Compacta Dopaminergic Neurons in Parkinson's Disease

D J Surmeier et al. Neuroscience. .
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Parkinson's disease (PD) is the second most common neurodegenerative disease in developed countries. The core motor symptoms are attributable to the degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc). Why these neurons succumb in PD is not clear. One potential clue has come from the observation that the engagement of L-type Ca²⁺ channels during autonomous pacemaking elevates the sensitivity of SNc DA neurons to mitochondrial toxins used to create animal models of PD, suggesting that Ca²⁺ entry is a factor in their selective vulnerability. Recent work has shown that this Ca²⁺ entry also elevates mitochondrial oxidant stress and that this stress is exacerbated by deletion of DJ-1, a gene associated with an early onset, recessive form of PD. Epidemiological data also support a linkage between L-type Ca²⁺ channels and the risk of developing PD. This review examines the hypothesis that the primary factor driving neurodegenerative changes in PD is the metabolic stress created by Ca²⁺ entry, particularly in the face of genetic or environmental factors that compromise oxidative defenses or proteostatic competence.

Conflict of interest statement

Disclosure: The authors have no competing financial interests


Figure 1
Figure 1. Pacemaking firing in SNc DA neurons is associated with Ca2+ influx via L-type channels
a) Macroscopic view of a coronal midbrain slice section illustrating the SNc region as the site of electrophysiological recording and optical imaging. b) SNc DA neurons illustrated by infrared digital interference contrast (IR-DIC) optics from coronal mibrain slices. c) Representative pacemaking firing trace in whole-cell patch current clamp configuration from an SNc DA neuron. d) From panel ‘c’, one scaled action potential spike showing that SNc DA neurons display broad action potentials compared to a GABAergic interneuron recorded from the substantia nigra pars reticulata (SNr). e) Ca2+ imaging of dendrites using two-photon laser scanning microscopy (2PLSM) in an SNc DA neuron displaying pacemaking firing synchronized to Ca2+ transients per spike in a distal dendrite (marked by the red dot). Experiments were performed as described previously. Blocking L-type channels with 5 μM isradipine attenuates dendritic Ca2+ transients without affecting pacemaking rate. f) Recording from a ventral tegmental area (VTA) DA neuron showing pacemaking firing but this population of cells lack dendritic Ca2+ oscillations. Figures e-f represents data adapted from previous work (Guzman et al., 2010).
Figure 2
Figure 2. SNc DA neurons display elevated oxidant stress attenuated by blockade of L-type Ca2+ channels
a) Representative confocal microscopy images from coronal midbrain slices of a transgenic mouse that expresses a mitochondrial redox-sensitive form of green fluorescent protein (mito-roGFP) under the regulation of the tyrosine hydroxylase promoter DNA sequence. b) Relative oxidation plots showing that SNc DA neurons (black trace) displays increased oxidation compared to VTA. Acute application of 5 μM isradipine (green trace) decrease oxidant stress with relative oxidation values closer to VTA neurons (blue trace). Relative oxidation plots are calculated by calibrating the mito-roGFP signal with dithiothreitol (DTT) and aldrithiol to fully reduce and oxidize the mito-roGFP signal respectively. Fluorescence values of the mito-roGFP under control conditions (F), DTT (FDTT), and aldrithiol (Fald) are taken from the same neuron, and relative oxidation is calculated by the following A value of 0 represents full equation: 1-[(F-Fald)/(FDTT-Fald)]. A value of 0 represents full reduction whereas a value of 1 represents full oxidation. c) Loss of function of DJ-1 protein (pink trace) exacerbated oxidant stress in SNc DA neurons compared to wild-type mice. Pretreatment of SNc DA neurons in DJ-1 knock-out mice with 200 nM isradipine decreased oxidant stress with relative oxidation values similar to naïve SNc DA neurons from wild-type mice. d) Representative 2PLSM image from an SNc DA neuron labeled with tetramethyl rhodamine methyl ester dyes to monitor mitochondrial membrane potential (MMP). e) SNc DA neurons have flickering changes of MMP that are absent in VTA DA neurons. The change in MMP in SNc DA neurons represents a 20% amplitude change in voltage. f) Gene-targeted deletion of DJ-1 reduced the amplitude and frequency of flickering mitochondrial activity. g) Blockade of L-type channels with isradipine (5 μM) decreased frequency of MMP flickering activity, suggesting that Ca2+ impacts the mild mitochondrial depolarization or uncoupling phenomena in SNc DA neurons. h) Antagonism of uncoupling proteins (UCPs) with 100 μM genipin decreased MMP flickering activity. i-j) SNc DA neurons containing mild depolarization of the MMP showed increased relative mRNA abundance of the uncoupling proteins UCP4 and UCP5 (gray bars). DJ-1 knock-out mice however, display decreased levels of UCP4 and UCP5 compared to WT, suggesting that the decreased amplitude and frequency changes in MMP in DJ-1 knock-out mice are related to a decrement in the proteins that induce uncoupling. This figure summarizes data adapted from previous work (Guzman et al., 2010).

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