Mitochondrial Pathology in Parkinson's Disease

Schapira, Anthony H.V.

doi:10.1002/msj.20303

Cited by 71 publications

(42 citation statements)

References 107 publications

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“…Conjugation to ubiquitin can have multiple effects including targeting of proteins to the proteasome or autophagosome, regulation of endocytosis, maintenance of synaptic function and alterations in mitochondrial dynamics (Chin et al, 2010, DiAntonio et al, 2004, Schapira, 2011, Schmidt et al, 2014). To test whether proteasome inhibition would mimic the neurotoxic effects of E1 ligase inhibition, we used two previously characterized dominant-negative proteasome subunits, Pros26 and Prosβ2 (Belote et al, 2002).…”

Section: 0 Resultsmentioning

confidence: 99%

“…Together, these studies raise the possibility that inhibition of E1 ligase is neurotoxic because of the disruption of ubiquitination-dependent processes other than protein degradation by the proteasome. These might include modifications of the aggresome-autophagy pathway, mitochondria fission and mitophagy, or alpha-synuclein aggregation (Beyer et al, 2013, Chin et al, 2010, Schapira, 2011). Important caveats to this interpretation include the possibility that the inhibitory proteasome subunits were insufficiently active in our studies.…”

Section: 0 Discussionmentioning

confidence: 99%

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Synergistic effects on dopamine cell death in a Drosophila model of chronic toxin exposure

et al. 2014

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The neurodegenerative effects of Parkinson’s disease (PD) are marked by a selective loss of dopaminergic (DA) neurons. Epidemiological studies suggest that chronic exposure to the pesticide paraquat may increase the risk for PD and DA cell loss. However, combined exposure with additional fungicide(s) including maneb and/or ziram may be required for pathogenesis. To explore potential pathogenic mechanisms, we have developed a Drosophila model of chronic paraquat exposure. We find that while chronic paraquat exposure alone decreased organismal survival and motor function, combined chronic exposure to both paraquat and maneb was required for DA cell death in the fly. To initiate mechanistic studies of this interaction, we used additional genetic reagents to target the ubiquitin proteasome system, implicated in some rare familial forms of PD and the toxic effects of ziram. Genetic inhibition of E1 ubiquitin ligase, but not the proteasome itself, increased DA cell death in combination with maneb but not paraquat. These studies establish a model for long-term exposure to multiple pesticides, and support the idea that pesticide interactions relevant to PD may involve inhibition of protein ubiquitination.

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Section: 0 Resultsmentioning

confidence: 99%

Section: 0 Discussionmentioning

confidence: 99%

Synergistic effects on dopamine cell death in a Drosophila model of chronic toxin exposure

et al. 2014

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“…The proposition that a neuronal phenotype leads to excessive mitochondrial oxidant stress, mitochondrial DNA deletion, and bioenergetic deficiency is consistent with a large body of evidence implicating these organelles in PD pathogenesis (Schapira 2011;Trancikova et al 2011). The following are important questions in that model that still need to be addressed: Does the oxidant stress extend from the mitochondria to other parts of the cell?…”

Section: Reconciliation With Current Models Of Pd Pathogenesismentioning

confidence: 96%

Physiological Phenotype and Vulnerability in Parkinson's Disease

Surmeier

Guzmán²,

Sánchez³

et al. 2012

Cold Spring Harbor Perspectives in Medicine

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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.

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“…Neurons are post-mitotic and non-proliferating cells; therefore, their mitochondria are particularly prone to accumulation of oxidative damage over time and high levels of Ca 2 þ influx in neurons may be a further stressor. Not surprisingly, mitochondrial damage and dysregulation of mitophagy have been implicated in several neurodegenerative disease associated with aging, such as PD, 100 Alzheimer's disease (AD), and Huntington's disease (HD). 101 Significantly, it is not clear whether it is the upregulation or downregulation of mitophagy that contributes to the pathology of some of these neurodegenerative diseases.…”

Section: Mitophagy In Neuronsmentioning

confidence: 99%

The pathways of mitophagy for quality control and clearance of mitochondria

2012

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Selective autophagy of mitochondria, known as mitophagy, is an important mitochondrial quality control mechanism that eliminates damaged mitochondria. Mitophagy also mediates removal of mitochondria from developing erythrocytes, and contributes to maternal inheritance of mitochondrial DNA through the elimination of sperm-derived mitochondria. Recent studies have identified specific regulators of mitophagy that ensure selective sequestration of mitochondria as cargo. In yeast, the mitochondrial outer membrane protein autophagy-related gene 32 (ATG32) recruits the autophagic machinery to mitochondria, while mammalian Nix is required for degradation of erythrocyte mitochondria. The elimination of damaged mitochondria in mammals is mediated by a pathway comprised of PTEN-induced putative protein kinase 1 (PINK1) and the E3 ubiquitin ligase Parkin. PINK1 and Parkin accumulate on damaged mitochondria, promote their segregation from the mitochondrial network, and target these organelles for autophagic degradation in a process that requires Parkin-dependent ubiquitination of mitochondrial proteins. Here we will review recent advances in our understanding of the different pathways of mitophagy. In addition, we will discuss the relevance of these pathways in neurons where defects in mitophagy have been implicated in neurodegeneration. Facts Mitophagy mediates clearance of damaged mitochondria, and is also involved in the removal of mitochondria from maturing erythrocytes and eliminating sperm-derived mitochondria after fertilization. In yeast, the mitochondrial outer membrane protein autophagy-related gene 32 (ATG32) recruits the core autophagic machinery to mitochondria for their selective removal. A pathway containing PTEN-induced putative protein kinase 1 (PINK1) and Parkin responds to loss of mitochondrial membrane potential by targeting damaged mitochondria for clearance. The PINK1/Parkin pathway is triggered when PINK1 is stabilized on the outer membrane of damaged mitochondria, where it facilitates recruitment of cytosolic Parkin. Damaged mitochondria are prevented from moving and fusing with the mitochondrial reticulum in preparation for their mitophagic clearance. Open QuestionsHow distinct are the mitophagy pathways triggered by different stimuli or conditions?To what extent does Parkin activate mitophagy by causing the degradation of mitochondrial surface proteins or hyperubiquitinating the mitochondrial surface? How do PINK1 and Parkin interact with one another and with substrates on the mitochondrial surface in causing mitophagy? In contrast to the remarkable conservation of the core autophagic machinery, why are mitophagy-specific genes so little conserved between yeast and mammals? How best should mitophagy be triggered by researchers probing physiologically relevant pathways?The mitochondrion is an important actor in the life of a eukaryotic cell, but, like all good actors, a mitochondrion needs to exit the stage at the right time. Mitophagy removes mitochondria once they have played their part. This artic...

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Mitochondrial Pathology in Parkinson's Disease

Cited by 71 publications

References 107 publications

Synergistic effects on dopamine cell death in a Drosophila model of chronic toxin exposure

Synergistic effects on dopamine cell death in a Drosophila model of chronic toxin exposure

Physiological Phenotype and Vulnerability in Parkinson's Disease

The pathways of mitophagy for quality control and clearance of mitochondria

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