Oxidative damage in nucleic acids and Parkinson's disease

Research output: Contribution to journalReview article

159 Citations (Scopus)

Abstract

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 H2O 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.

Original languageEnglish
Pages (from-to)919-934
Number of pages16
JournalJournal of Neuroscience Research
Volume85
Issue number5
DOIs
Publication statusPublished - Apr 1 2007

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Mitochondrial DNA
Nucleic Acids
DNA Glycosylases
Parkinson Disease
Dopaminergic Neurons
Purine Nucleosides
Corpus Striatum
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Mitochondrial Genome
Adenine
Enzymes
Genes
Rodentia
Mitochondria
Oxidative Stress
Cell Death
Fibroblasts
Electrons
DNA
Brain

All Science Journal Classification (ASJC) codes

  • Cellular and Molecular Neuroscience

Cite this

Oxidative damage in nucleic acids and Parkinson's disease. / Nakabeppu, Yusaku; Tsuchimoto, Daisuke; yamaguchi, hiroo; Kunihiko, Sakumi.

In: Journal of Neuroscience Research, Vol. 85, No. 5, 01.04.2007, p. 919-934.

Research output: Contribution to journalReview article

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