Mitochondrial dysfunction in the limelight of Parkinson's disease pathogenesis

Banerjee, Rebecca; Starkov, Anatoly A.; Beal, M. Flint; Thomas, Bobby

doi:10.1016/j.bbadis.2008.11.007

Cited by 232 publications

(188 citation statements)

References 228 publications

(247 reference statements)

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“…These symptoms are caused by the death of neurons in a region of the midbrain called the substantia nigra. The neurons that survive in this region exhibit a defect in complex I of the mitochondrial electron transport chain and show signs of oxidative damage (2)(3)(4). In addition, surviving neurons contain characteristic cytosolic inclusions named "Lewy bodies" that are enriched with aggregated forms of the presynaptic protein ␣-synuclein (aSyn) (5).…”

Section: Parkinson's Disease (Pd)mentioning

confidence: 99%

“…In addition, surviving neurons contain characteristic cytosolic inclusions named "Lewy bodies" that are enriched with aggregated forms of the presynaptic protein ␣-synuclein (aSyn) (5). It is hypothesized that reactive oxygen species (ROS) accumulate as a result of mitochondrial impairment and contribute to neurodegeneration by causing the oxidation of lipid, proteins, and DNA (2)(3)(4). A buildup of ROS may promote the formation of harmful aSyn aggregates in the brains of PD patients (6 -8).…”

Section: Parkinson's Disease (Pd)mentioning

confidence: 99%

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Effect of Single Amino Acid Substitution on Oxidative Modifications of the Parkinson’s Disease-Related Protein, DJ-1

Madian

Hindupur

Hulleman

et al. 2012

Molecular & Cellular Proteomics

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Mutations in the gene encoding DJ-1 have been identified in patients with familial Parkinson's disease (PD) and are thought to inactivate a neuroprotective function. Oxidation of the sulfhydryl group to a sulfinic acid on cysteine residue C106 of DJ-1 yields the "2O " form, a variant of the protein with enhanced neuroprotective function. We hypothesized that some familial mutations disrupt DJ-1 activity by interfering with conversion of the protein to the 2O form. To address this hypothesis, we developed a novel quantitative mass spectrometry approach to measure relative changes in oxidation at specific sites in mutant DJ-1 as compared with the wild-type protein. Treatment of recombinant wild-type DJ-1 with a 10-fold molar excess of H 2 O 2 resulted in a robust oxidation of C106 to the sulfinic acid, whereas this modification was not detected in a sample of the familial PD mutant M26I exposed to identical conditions. Methionine oxidized isoforms of wild-type DJ-1 were depleted, presumably as a result of misfolding and aggregation, under conditions that normally promote conversion of the protein to the 2O form. These data suggest that the M26I familial substitution and methionine oxidation characteristic of sporadic PD may disrupt DJ-1 function by disfavoring a site-specific modification required for optimal neuroprotective activity. Our findings indicate that a single amino acid substitution can markedly alter a protein's ability to undergo oxidative modification, and they imply that stimulating the

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Section: Parkinson's Disease (Pd)mentioning

confidence: 99%

Section: Parkinson's Disease (Pd)mentioning

confidence: 99%

Effect of Single Amino Acid Substitution on Oxidative Modifications of the Parkinson’s Disease-Related Protein, DJ-1

Madian

Hindupur

Hulleman

et al. 2012

Molecular & Cellular Proteomics

View full text Add to dashboard Cite

show abstract

“…However, claims that the mPTP fulfills a causative role in PD remain poorly substantiated on [93]. For example, studies reporting an increased generation of ROS in PD-related mPTP dysfunction has been criticized for only making use of exogenously applied oxidants, while the role of endogenous ROS in mPTP activation remains unknown [94].…”

Section: Defective Mitochondrial Permeability Transition Pore As a Comentioning

confidence: 99%

Mitochondrial proteomics as a selective tool for unraveling Parkinson’s disease pathogenesis

Pienaar¹,

Dexter²,

Burkhard³

2010

Expert Review of Proteomics

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“…One of the well-known pathogenic mechanisms in PD is mitochondrial dysfunction (29). Impaired mitochondrial content of toxic reactive oxygen species may cause damage to neurons and it has been shown that mitophagy eliminates these defective mitochondria and protects the neurons from their negative effects (30).…”

Section: Role Of Autophagy In the Pathogenesis Of Neurodegenerative Dmentioning

confidence: 99%

Role of autophagy in the pathogenesis of Alzheimer disease

Ülger¹

2015

Turk J Med Sci

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IntroductionAlzheimer disease (AD) is mainly characterized by progressive degeneration of the brain cells and leads to irreversible decline in cognitive abilities. The major pathological factor of this disorder is accumulation of amyloid-β (Aβ) protein in the cortex and hippocampal area, resulting in cognitive impairment and memory loss. Researches on therapeutic strategies for AD have mainly focused on anti-Aβ strategies, but most recently, studies examining the effect of monoclonal antibodies against Aβ protein such as solanezumab and bapineuzumab have resulted in disappointment due to high toxicity or ineffectiveness (1,2).Autophagy is thought to be one of the cleaving systems clearing toxic Aβ proteins from neurons. This pathway sustains cell life by protecting cells against deprivation and other threatening stressors (3). Another hallmark pathological process in AD is accumulation of hyperphosphorylated tau protein in the brain, resulting in neurofibrillary tangles. Autophagy is an inhibitor of the mammalian target of rapamycin (mTOR) induction pathway, which has been shown to be a promoter of hyperphosphorylation and accumulation of tau proteins (4).There is growing clinical and preclinical evidence about association of autophagy and AD in the literature, but none of these studies have succeeded in showing a link between autophagy and modulation of the disease progression yet (5). In this review, the importance of autophagy in AD pathogenesis will be discussed in light of the current knowledge in the literature. Definition and mechanisms of autophagyAutophagy is a process of self-digestion. It is thought to be a response to stressors and it allows cells to adapt to environmental changes (6). Deprivations in cell conditions may cause induction of autophagy to provide energy for the synthesis of essential substrates that are important for survival of organelles and cells (7). Since de Duve first described autophagy in 1963, our knowledge about this issue has continued to grow, especially in the last decade (6). Today it is thought that there is an association between autophagy and some disorders like cancer, infectious disease, and neurodegenerative disorders (8).Sequestration in the autophagy process first begins with the formation of a phagophore (Figure) (9). It then expands into a double-membrane autophagosome and surrounds a portion of the cytoplasm (6). Endosome, the product of endocytosis, fuses with the autophagosome, and this new product is called an amphisome (6). The autophagosome or amphisome fuses with a lysosome Abstract: Alzheimer disease (AD) is the most common progressive neurodegenerative disorder causing increased morbidity and mortality. It is characterized by accumulation of amyloid-β in neurons. As there is no known definitive treatment of this disorder, studies trying to determine its exact pathogenetic pathways and target therapies for these specific pathways are being rapidly conducted. Autophagy is one of the areas of interest in studies on the pathogenesis of AD. It is a process of ...

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Mitochondrial dysfunction in the limelight of Parkinson's disease pathogenesis

Cited by 232 publications

References 228 publications

Effect of Single Amino Acid Substitution on Oxidative Modifications of the Parkinson’s Disease-Related Protein, DJ-1

Effect of Single Amino Acid Substitution on Oxidative Modifications of the Parkinson’s Disease-Related Protein, DJ-1

Mitochondrial proteomics as a selective tool for unraveling Parkinson’s disease pathogenesis

Role of autophagy in the pathogenesis of Alzheimer disease

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