Oxidative damage in nucleic acids and Parkinson's disease

Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
Journal of Neuroscience Research (Impact Factor: 2.59). 04/2007; 85(5):919-34. DOI: 10.1002/jnr.21191
Source: PubMed


Oxidative DNA lesions, such as 8-oxoguanine (8-oxoG), accumulate in nuclear and mitochondrial genomes during aging, and such accumulation can increase dramatically in patients with Parkinson's disease (PD). To counteract oxidative damage to nucleic acids, human and rodents are equipped with three distinct enzymes. One of these, MTH1, hydrolyzes oxidized purine nucleoside triphosphates, such as 8-oxo-2'-deoxyguanosine triphosphate and 2-hydroxy-2'-deoxyadenosine triphosphate, to their monophosphate forms. The other two enzymes are 8-oxoG DNA glycosylase encoded by the OGG1 gene and adenine/2-hydroxyadenine DNA glycosylase encoded by the MUTYH gene. We have shown a significant increase in 8-oxoG in mitochondrial DNA as well as an elevated expression of MTH1, OGG1, and MUTYH in nigrostriatal dopaminergic neurons of PD patients, suggesting that the buildup of these lesions may cause dopamine neuron loss. We established MTH1-null mice and found that MTH1-null fibroblasts were highly susceptible to cell death caused by H(2)O(2) characterized by pyknosis and electron-dense deposits in the mitochondria, and that this was accompanied by an ongoing accumulation of 8-oxoG in nuclear and mitochondrial DNA. We also showed that MTH1-null mice exhibited an increased accumulation of 8-oxoG in striatal mitochondrial DNA, followed by more extreme neuronal dysfunction after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration than that of wild-type mice. In conclusion, oxidative damage in nucleic acids is likely to be a major risk factor for Parkinson's disease, indicating that a solid understanding of the defense mechanisms involved will enable us to develop new strategies for protecting the brain against oxidative stress.

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Available from: Yusaku Nakabeppu,
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    • "This, and the down-regulation of the superoxide dismutase, glutatione peroxidase, DAT and vesicular monoamine transporter 2 activities observed in PD (Riederer et al., 1989; Zeevalk et al., 2008), suggest high oxidative stress in the SN of these patients. This possibility is also supported by the high oxidative damage of lipids (Bosco et al., 2006), proteins and DNA (Nakabeppu et al., 2007) found in the SN of these patients (Jenner, 2007). However, all these facts have also been observed in the aged brain and cannot be considered as a selective characteristic of the PD brain (Sohal and Brunk, 1992; Oliveira et al., 2010). "
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    ABSTRACT: Available data show marked similarities for the degeneration of dopamine cells in Parkinson's disease (PD) and aging. The etio-pathogenic agents involved are very similar in both cases, and include free radicals, different mitochondrial disturbances, alterations of the mitophagy and the ubiquitin-proteasome system. Proteins involved in PD such as α-synuclein, UCH-L1, PINK1 or DJ-1, are also involved in aging. The anomalous behavior of astrocytes, microglia and stem cells of the subventricular zone (SVZ) also changes similarly in aging brains and PD. Present data suggest that PD could be the expression of aging on a cell population with high vulnerability to aging. The future knowledge of mechanisms involved in aging could be critical for both understanding the etiology of PD and developing etiologic treatments to prevent the onset of this neurodegenerative illness and to control its progression.
    Frontiers in Neuroanatomy 08/2014; 8:80. DOI:10.3389/fnana.2014.00080 · 3.54 Impact Factor
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    • "Despite PD being a complex and multifactorial disease, oxidative stress and mitochondrial dysfunction are thought to be major causes of neurodegeneration in PD [4]. In both idiopathic and genetic PD, oxidative stress is thought to be a common denominator and the substantia nigra of PD subjects exhibit increased levels of oxidized lipids [5], proteins and DNA [6] and decreased levels of reduced glutathione (GSH) [7]. "
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    ABSTRACT: Background Parkinson’s disease (PD) is the second most common neurodegenerative movement disorder, caused by preferential dopaminergic neuronal cell death in the substantia nigra, a process also influenced by oxidative stress. L-3,4-dihydroxyphenylalanine (L-DOPA) represents the main treatment route for motor symptoms associated with PD however, its exact mode of action remains unclear. A spectrum of conflicting data suggests that L-DOPA may damage dopaminergic neurons due to oxidative stress whilst other data suggest that L-DOPA itself may induce low levels of oxidative stress, which in turn stimulates endogenous antioxidant mechanisms and neuroprotection. Results In this study we performed a two-dimensional gel electrophoresis (2DE)-based proteomic study to gain further insight into the mechanism by which L-DOPA can influence the toxic effects of H2O2 in neuronal cells. We observed that oxidative stress affects metabolic pathways as well as cytoskeletal integrity and that neuronal cells respond to oxidative conditions by enhancing numerous survival pathways. Our study underlines the complex nature of L-DOPA in PD and sheds light on the interplay between oxidative stress and L-DOPA. Conclusions Oxidative stress changes neuronal metabolic routes and affects cytoskeletal integrity. Further, L-DOPA appears to reverse some H2O2-mediated effects evident at both the proteome and cellular level.
    BMC Neuroscience 07/2014; 15(1):93. DOI:10.1186/1471-2202-15-93 · 2.67 Impact Factor
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    • "decline in hepatic blood flow and clearance capacity of metabolized compounds. Several studies have linked brain and liver aging to DNA instability, particularly of mitochondrial DNA (mtDNA) and to increasing accumulation of oxidative lesions and mutations (López-Torres et al. 2002; Coskun et al. 2004; Smigrodzki et al. 2004; Markesbery and Lovell 2006; Nakabeppu et al. 2007; Castro et al. 2012). "
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    ABSTRACT: Changes in the endocrine system have been suggested to act as signaling factors in the regulation of age-related events. Among the different hormones that have been linked to the aging process, estrogens have been widely investigated. They have been associated with inflammatory and oxidative processes and several investigations have established a relationship between the protective effects of estrogens and the mitochondrial function. Mitochondrial DNA is subjected to continuous oxidative attack by free radicals, and the base excision repair (BER) pathway is the main DNA repair route present in mitochondria. We have investigated the effect of estrogen levels on some of the key enzymes of BER in brain and liver mitochondria. In both tissues, depletion of estrogens led to an increased mitochondrial AP endonuclease (mtAPE1) activity, while restoration of estrogen levels by exogenous supplementation resulted in restitution of control APE1 activity only in liver. Moreover, in hepatic mitochondria, changes in estrogen levels affected the processing of oxidative lesions but not deaminations. Our results suggest that changes in mtAPE1 activity are related to specific translocation of the enzyme from the cytosol into the mitochondria probably due to oxidative stress changes as a consequence of changes in estrogen levels.
    Biogerontology 05/2013; 14(4). DOI:10.1007/s10522-013-9431-x · 3.29 Impact Factor
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