Calcium, Dopamine and Neuronal Calcium Sensor 1: Their Contribution to Parkinson’s Disease (original) (raw)
Related papers
Calcium entry induces mitochondrial oxidant stress in vagal neurons at risk in Parkinson's disease
Nature Neuroscience, 2012
Mitochondrial oxidant stress is widely viewed as critical to pathogenesis in Parkinson's disease. But the origins of this stress are poorly defined. One possibility is that it arises from the metabolic demands associated with regenerative activity. To test this hypothesis, neurons in the dorsal motor nucleus of the vagus (DMV), a population cholinergic neurons that shows signs of pathology in the early stages of Parkinson's disease, were characterized in mouse brain slices. DMV neurons were slow, autonomous pacemakers with broad spikes, leading to calcium entry that was weakly buffered. Using a novel transgenic mouse expressing a redox-sensitive optical probe targeted to the mitochondrial matrix, it was found that calcium entry during pacemaking created a basal mitochondrial oxidant stress. Knocking out DJ-1 -a gene associated with early-onset Parkinson's disease -exacerbated this stress. These results point to a common mechanism underlying mitochondrial oxidant stress in Parkinson's disease and a therapeutic strategy to ameliorate it.
Neuron, 2009
The basis for selective death of specific neuronal populations in neurodegenerative diseases remains unclear. Parkinson's disease (PD) is a synucleinopathy characterized by a preferential loss of dopaminergic neurons in the substantia nigra (SN), whereas neurons of the ventral tegmental area (VTA) are spared. Using intracellular patch electrochemistry to directly measure cytosolic dopamine (DA cyt ) in cultured midbrain neurons, we confirm that elevated DA cyt and its metabolites are neurotoxic and that genetic and pharmacological interventions that decrease DA cyt provide neuroprotection. L-DOPA increased DA cyt in SN neurons to levels 2-3-fold higher than in VTA neurons, a response dependent on dihydropyridine-sensitive Ca 2+ channels, resulting in greater susceptibility of SN neurons to L-DOPA-induced neurotoxicity. DA cyt was not altered by α-synuclein deletion, although dopaminergic neurons lacking α-synuclein were resistant to L-DOPA-induced cell death. Thus, an interaction between Ca 2+ , DA cyt and α-synuclein may underlie the susceptibility of SN neurons in PD, suggesting multiple therapeutic targets.
Neuron, 2009
The basis for selective death of specific neuronal populations in neurodegenerative diseases remains unclear. Parkinson's disease (PD) is a synucleinopathy characterized by a preferential loss of dopaminergic neurons in the substantia nigra (SN), whereas neurons of the ventral tegmental area (VTA) are spared. Using intracellular patch electrochemistry to directly measure cytosolic dopamine (DA cyt ) in cultured midbrain neurons, we confirm that elevated DA cyt and its metabolites are neurotoxic and that genetic and pharmacological interventions that decrease DA cyt provide neuroprotection. L-DOPA increased DA cyt in SN neurons to levels 2-3-fold higher than in VTA neurons, a response dependent on dihydropyridine-sensitive Ca 2+ channels, resulting in greater susceptibility of SN neurons to L-DOPA-induced neurotoxicity. DA cyt was not altered by α-synuclein deletion, although dopaminergic neurons lacking α-synuclein were resistant to L-DOPA-induced cell death. Thus, an interaction between Ca 2+ , DA cyt and α-synuclein may underlie the susceptibility of SN neurons in PD, suggesting multiple therapeutic targets.
Science's STKE, 2006
Parkinson’s disease (PD) is a common neurodegenerative disorder that is most often sporadic, but in some cases it can be inherited as a simple Mendelian trait. The most important pathological feature of the disease is the death of brainstem dopaminergic neurons in the substantia nigra, which leads to characteristic motor symptoms. The etiology of PD remains unknown, but mitochondrial dysfunction and oxidative stress may contribute actively to the underlying pathomechanism. New studies suggest that K ATP channel activation may represent a downstream effector of these two cellular anomalies.
The Origins of Oxidant Stress in Parkinson's Disease and Therapeutic Strategies
Antioxidants & Redox Signaling, 2011
Parkinson's disease (PD) is a major world-wide health problem afflicting millions of the aged population. Factors that act on most or all cell types (pan-cellular factors), particularly genetic mutations and environmental toxins, have dominated public discussions of disease etiology. Although there is compelling evidence supporting an association between disease risk and these factors, the pattern of neuronal pathology and cell loss is difficult to explain without cell-specific factors. This article focuses on recent studies showing that the neurons at greatest risk in PD-substantia nigra pars compacta dopamine neurons-have a distinctive physiological phenotype that could contribute to their vulnerability. The opening of L-type calcium channels during autonomous pacemaking results in sustained calcium entry into the cytoplasm of substantia nigra pars compacta dopamine neurons, resulting in elevated mitochondrial oxidant stress and susceptibility to toxins used to create animal models of PD. This cellspecific stress could increase the negative consequences of pan-cellular factors that broadly challenge either mitochondrial or proteostatic competence. The availability of well-tolerated, orally deliverable antagonists for L-type calcium channels points to a novel neuroprotective strategy that could complement current attempts to boost mitochondrial function in the early stages of the disease.
Mitochondria, calcium, and endoplasmic reticulum stress in Parkinson's disease
BioFactors, 2011
Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by a loss of dopaminergic neurons in the substantia nigra pars compacta (SNPC) and the presence of intracytoplasmatic inclusions known as Lewy bodies, largely composed of alpha-synuclein (a-syn). PD is a multifactorial disease and its etiology remains largely elusive. Although more than 90% of the cases are sporadic, mutations in several nuclear encoded genes have been linked to the development of autosomal recessive and dominant familial parkinsonian syndromes (Bogaerts et al. (2008) Genes Brain Behav 7, 129-151), enhancing our understanding of biochemical and cellular mechanisms contributing to the disease. Many cellular mechanisms are thought to be involved in the dopaminergic neuronal death in PD, including oxidative stress, intracellular Ca 2þ homeostasis impairment, and mitochondrial dysfunctions. Furthermore, endoplasmic reticulum (ER) stress together with abnormal protein degradation by the ubiquitin proteasome system is considered to contribute to the PD pathogenesis. This review covers all the aspects related to the molecular mechanisms underlying the interplay between mitochondria, ER, and proteasome system in PD-associated neurodegeneration.
Dopamine induced neurodegeneration in a PINK1 model of Parkinson's disease
PLoS ONE, 2012
Background: Parkinson's disease is a common neurodegenerative disease characterised by progressive loss of dopaminergic neurons, leading to dopamine depletion in the striatum. Mutations in the PINK1 gene cause an autosomal recessive form of Parkinson's disease. Loss of PINK1 function causes mitochondrial dysfunction, increased reactive oxygen species production and calcium dysregulation, which increases susceptibility to neuronal death in Parkinson's disease. The basis of neuronal vulnerability to dopamine in Parkinson's disease is not well understood.
Molecular cell, 2009
Mutations in PINK1 cause autosomal recessive Parkinson's disease. PINK1 is a mitochondrial kinase of unknown function. We investigated calcium homeostasis and mitochondrial function in PINK1deficient mammalian neurons. We demonstrate physiologically that PINK1 regulates calcium efflux from the mitochondria via the mitochondrial Na + /Ca 2+ exchanger. PINK1 deficiency causes mitochondrial accumulation of calcium, resulting in mitochondrial calcium overload. We show that calcium overload stimulates reactive oxygen species (ROS) production via NADPH oxidase. ROS production inhibits the glucose transporter, reducing substrate delivery and causing impaired respiration. We demonstrate that impaired respiration may be restored by provision of mitochondrial complex I and II substrates. Taken together, reduced mitochondrial calcium capacity and increased ROS lower the threshold of opening of the mitochondrial permeability transition pore (mPTP) such that physiological calcium stimuli become sufficient to induce mPTP opening in PINK1-deficient cells. Our findings propose a mechanism by which PINK1 dysfunction renders neurons vulnerable to cell death.
Journal of Neurochemistry, 2002
Parkinson's disease may be linked to defects in mitochondrial function. Mitochondrially transformed cells (cybrids) were created from Parkinson's disease patients or disease-free controls. Parkinson's disease cybrids had 26% less complex I activity, but maintained comparable basal calcium and energy levels. Parkinson's disease cybrids recovered from a carbachol-induced increase in cytosolic calcium 53% more slowly than controls even with lanthanum and thapsigargin blockade. Inhibition of complex I with the Parkinson's disease-inducing metabolite 1 -methyl-4-phenylpyridinium (MPP~)similarly reduced the rate of recovery after carbachol. This MPP~-induced reduction in recovery rates was much more pronounced in control cybrids than in Parkinson's disease cybrids. Parkinson's disease cybrids had less carbonyl cyanide m-chlorophenylhydrazone-releasable calcium. Bypassing complex I with succinate partially restored Parkinson's disease cybrid, and MPP~suppressed control cybrid recovery rates. The subtle alteration in calcium homeostasis of Parkinson's disease cybrids may reflect an increased susceptibility to cell death under circumstances not ordinarily toxic. Key Words: Parkinson's disease-Mitochondria-Calcium.
Understanding Dopaminergic Cell Death Pathways in Parkinson Disease
Neuron, 2016
Parkinson disease (PD) is a multifactorial neurodegenerative disorder, the etiology of which remains largely unknown. Progressive impairment of voluntary motor control, which represents the primary clinical feature of the disease, is caused by a loss of midbrain substantia nigra dopamine (DA) neurons. We present here a synthetic overview of cell-autonomous mechanisms that are likely to participate in DA cell death in both sporadic and inherited forms of the disease. In particular, we describe how damage to vulnerable DA neurons may arise from cellular disturbances produced by protein misfolding and aggregation, disruption of autophagic catabolism, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, or loss of calcium homeostasis. Where pertinent, we show how these mechanisms may mutually cooperate to promote neuronal death.