Oxidative damage to macromolecules in human Parkinson disease and the rotenone model.
TL;DR: The recent evidence for oxidative damage to nucleic acids, lipids, and proteins in both the brain and the peripheral tissues in human PD and in the rotenone model is reviewed.
About: This article is published in Free Radical Biology and Medicine.The article was published on 2013-09-01 and is currently open access. It has received 280 citations till now. The article focuses on the topics: Oxidative stress & Neurodegeneration.
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TL;DR: This review focuses on biochemical concepts of lipidPeroxidation, production, metabolism, and signaling mechanisms of two main omega-6 fatty acids lipid peroxidation products: malondialdehyde (MDA) and, in particular, 4-hydroxy-2-nonenal (4-HNE), summarizing not only its physiological and protective function as signaling molecule stimulating gene expression and cell survival, but also its cytotoxic role inhibiting geneexpression and promoting cell death.
Abstract: Lipid peroxidation can be described generally as a process under which oxidants such as free radicals attack lipids containing carbon-carbon double bond(s), especially polyunsaturated fatty acids (PUFAs). Over the last four decades, an extensive body of literature regarding lipid peroxidation has shown its important role in cell biology and human health. Since the early 1970s, the total published research articles on the topic of lipid peroxidation was 98 (1970–1974) and has been increasing at almost 135-fold, by up to 13165 in last 4 years (2010–2013). New discoveries about the involvement in cellular physiology and pathology, as well as the control of lipid peroxidation, continue to emerge every day. Given the enormity of this field, this review focuses on biochemical concepts of lipid peroxidation, production, metabolism, and signaling mechanisms of two main omega-6 fatty acids lipid peroxidation products: malondialdehyde (MDA) and, in particular, 4-hydroxy-2-nonenal (4-HNE), summarizing not only its physiological and protective function as signaling molecule stimulating gene expression and cell survival, but also its cytotoxic role inhibiting gene expression and promoting cell death. Finally, overviews of in vivo mammalian model systems used to study the lipid peroxidation process, and common pathological processes linked to MDA and 4-HNE are shown.
3,647 citations
Additional excerpts
...[114] L....
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...Alzheimer’s disease MDA 4-HNE [104–113] [81, 108, 114–121]...
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...Parkinson’s disease MDA 4-HNE [81, 108, 114–121] [72, 114, 131, 135, 142, 170–174]...
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TL;DR: In this paper, the authors reviewed reported analytical methods and their principles for the quantitative measurement of MDA, HNE and 15(S)-8-iso-PGF2α in biological samples including plasma and urine, and critically discusses their biological and biomedical outcome which is rarely crystal clear and free of artefacts.
978 citations
Cites background from "Oxidative damage to macromolecules ..."
...As to the effects of anti-oxidants in the Parkinson disease, Sanders and Greenamyre concluded that the applied strategies have had limited success in clinical trials [98]....
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...In a recent article, Sanders and Greenamyre reviewed and discussed the oxidative damage to macromolecules in the human Parkinson disease and in the animal rotenone model [98]....
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TL;DR: This review examines the generation of reactive oxygen species by mammalian mitochondria, and the status of different sites of production in redox signaling and pathology, and identifies specific suppressors of two sites that allow the cellular roles of mitochondrial superoxide/hydrogen peroxide production to be investigated without catastrophic confounding bioenergetic effects.
694 citations
TL;DR: The effects of the drug-induced modulation of oxidative balance, and pharmacotherapeutic strategies for OS reduction are analyzed, and they are explored.
Abstract: The pathophysiologies of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), and Alzheimer’s disease (AD), are far from being fully explained. Oxidative stress (OS) has been proposed as one factor that plays a potential role in the pathogenesis of neurodegenerative disorders. Clinical and preclinical studies indicate that neurodegenerative diseases are characterized by higher levels of OS biomarkers and by lower levels of antioxidant defense biomarkers in the brain and peripheral tissues. In this article, we review the current knowledge regarding the involvement of OS in neurodegenerative diseases, based on clinical trials and animal studies. In addition, we analyze the effects of the drug-induced modulation of oxidative balance, and we explore pharmacotherapeutic strategies for OS reduction.
463 citations
TL;DR: This review presents evidence, gathered over the last decade, concerning a variety of pathogenic proteins, their important signaling pathways and pathogenic mechanisms associated with oxidative stress in Parkinson's disease and Alzheimer's disease, and emphasizes antioxidative options.
444 citations
Cites background from "Oxidative damage to macromolecules ..."
...Sanders and Greenamyre gave a more comprehensive summary and study about the oxidative damage to these macromolecules in human PD and in the rotenone model, which leaded to the interplay of secondary damage to other biomolecules (Sanders and Greenamyre, 2013)....
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References
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Book•
13 Jun 1985
TL;DR: 1. Oxygen is a toxic gas - an introduction to oxygen toxicity and reactive species, and the chemistry of free radicals and related 'reactive species'
Abstract: 1. Oxygen is a toxic gas - an introductionto oxygen toxicity and reactive species 2. The chemistry of free radicals and related 'reactive species' 3. Antioxidant defences Endogenous and Diet Derived 4. Cellular responses to oxidative stress: adaptation, damage, repair, senescence and death 5. Measurement of reactive species 6. Reactive species can pose special problems needing special solutions. Some examples. 7. Reactive species can be useful some more examples 8. Reactive species can be poisonous: their role in toxicology 9. Reactive species and disease: fact, fiction or filibuster? 10. Ageing, nutrition, disease, and therapy: A role for antioxidants?
21,528 citations
TL;DR: It seems possible that one factor in aging may be related to deleterious side attacks of free radicals (which are normally produced in the course of cellular metabolism) on cell constituents.
Abstract: The phenomenon of growth, decline and death—aging—has been the source of considerable speculation (1, 8, 10). This cycle seems to be a more or less direct function of the metabolic rate and this in turn depends on the species (animal or plant) on which are superimposed the factors of heredity and the effects of the stresses and strains of life—which alter the metabolic activity. The universality of this phenomenon suggests that the reactions which cause it are basically the same in all living things. Viewing this process in the light of present day free radical and radiation chemistry and of radiobiology, it seems possible that one factor in aging may be related to deleterious side attacks of free radicals (which are normally produced in the course of cellular metabolism) on cell constituents.* Irradiation of living things induces mutation, cancer, and aging (9). Inasmuch as these also arise spontaneously in nature, it is natural to inquire if the processes might not be similar. It is believed that one mechanism of irradiation effect is through liberation of OH and HO 2 radicals (12). There is evidence, although indirect, that these two highly active free radicals are produced normally in living systems. In the first place, free radicals are present in living cells; this was recently demonstrated in vivo by a paramagnetic resonance absorption method (3). Further, it was shown that the concentration of free radicals increased with increasing metabolic activity in conformity with the postulates set forth some years ago that free radicals were involved in biologic oxidation-reduction reactions (11, 13). Are some of these free radicals OH and/or HO2, or radicals of a similar high order of reactivity, and where might they arise in the cell? The most likely source of OH and HO2 radicals, at least in the animal cell, would be the interaction of the respiratory enzymes involved
7,917 citations
"Oxidative damage to macromolecules ..." refers background in this paper
...3 ical; ATP, adenosine-50-triphosphate; ROS, reactive oxygen species; ETC, electron transport chain; PD, Parkinson amine; LB, Lewy body; L-DOPA, levodopa, l-3,4-dihydroxyphenylalanine; VTA, ventral tegmental area; PUFA, MDA, malondialdehyde; HNE, 4-hydroxy-2-nonenal; mtDNA, mitochondrial DNA namyre). othy Greenamyre, J. Oxidative damage to macromolecules in human Parkinson disease and ....
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...ROS may also damage other proteins in the mitochondria, as well as other macromolecules....
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...Direct measurement of ROS is often difficult because of their short life span and there is not a practical method for ROS measurement in the living human brain....
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...In a seminal paper in 1956, Denham Harman first proposed that oxygen radicals were responsible for the damaging effects of O2, and since then, the free radical theory of aging has expanded to include the mitochondrion’s role in the production of ROS [7]....
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...For instance, damage to proteins can occur directly from ROS or by attack from the end-products of lipid peroxidation....
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TL;DR: Mutations in the newly identified gene appear to be responsible for the pathogenesis of Autosomal recessive juvenile parkinsonism, and the protein product is named ‘Parkin’.
Abstract: Parkinson's disease is a common neurodegenerative disease with complex clinical features1. Autosomal recessive juvenile parkinsonism (AR-JP)2,3 maps to the long arm of chromosome 6 (6q25.2-q27) and is linked strongly to the markers D6S305 and D6S253 (ref. 4); the former is deleted in one Japanese AR-JP patient5. By positional cloning within this microdeletion, we have now isolated a complementary DNA clone of 2,960 base pairs with a 1,395-base-pair open reading frame, encoding a protein of 465 amino acids with moderate similarity to ubiquitin at the amino terminus and a RING-finger motif at the carboxy terminus. The gene spans more than 500 kilobases and has 12 exons, five of which (exons 3–7) are deleted in the patient. Four other AR-JP patients from three unrelated families have a deletion affecting exon 4 alone. A 4.5-kilobase transcript that is expressed in many human tissues but is abundant in the brain, including the substantia nigra, is shorter in brain tissue from one of the groups of exon-4-deleted patients. Mutations in the newly identified gene appear to be responsible for the pathogenesis of AR-JP, and we have therefore named the protein product ‘Parkin’.
4,922 citations
"Oxidative damage to macromolecules ..." refers background in this paper
...Mutations in the ubiquitin carboxy-terminal hydrolase L1 (UCHL1) gene have also been linked to PD [93]....
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TL;DR: It is argued that modulating the unique redox regulatory mechanisms of cancer cells might be an effective strategy to eliminate these cells.
Abstract: Increased generation of reactive oxygen species (ROS) and an altered redox status have long been observed in cancer cells, and recent studies suggest that this biochemical property of cancer cells can be exploited for therapeutic benefits. Cancer cells in advanced stage tumours frequently exhibit multiple genetic alterations and high oxidative stress, suggesting that it might be possible to preferentially eliminate these cells by pharmacological ROS insults. However, the upregulation of antioxidant capacity in adaptation to intrinsic oxidative stress in cancer cells can confer drug resistance. Abrogation of such drug-resistant mechanisms by redox modulation could have significant therapeutic implications. We argue that modulating the unique redox regulatory mechanisms of cancer cells might be an effective strategy to eliminate these cells.
4,369 citations
TL;DR: It is reported that chronic, systemic inhibition of complex I by the lipophilic pesticide, rotenone, causes highly selective nigrostriatal dopaminergic degeneration that is associated behaviorally with hypokinesia and rigidity.
Abstract: The cause of Parkinson's disease (PD) is unknown, but epidemiological studies suggest an association with pesticides and other environmental toxins, and biochemical studies implicate a systemic defect in mitochondrial complex I. We report that chronic, systemic inhibition of complex I by the lipophilic pesticide, rotenone, causes highly selective nigrostriatal dopaminergic degeneration that is associated behaviorally with hypokinesia and rigidity. Nigral neurons in rotenone-treated rats accumulate fibrillar cytoplasmic inclusions that contain ubiquitin and alpha-synuclein. These results indicate that chronic exposure to a common pesticide can reproduce the anatomical, neurochemical, behavioral and neuropathological features of PD.
3,472 citations
"Oxidative damage to macromolecules ..." refers background in this paper
...The rotenone model of PD was developed in an effort to experimentally model in vivo nigrostriatal dopaminergic degeneration, LB formation, a systemic complex I defect, and the potential relevance of pesticide exposure to PD [132]....
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...Rotenone is a prototypical example of how an exogenous toxin can mimic clinical and pathological features of PD in an animal model [132,133]....
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...a-Synuclein- and polyubiquitin-containing LBs and Lewy neurites have also been observed in vivo [132,133]....
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...netic and had postural instability [132]....
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