Identification and characterization of OGG1 mutations in patients with Alzheimer's disease

Guogen Mao, Xiaoyu Pan, Bei Bei Zhu, Yanbin Zhang, Fenghua Yuan, Jian Huang, Mark A. Lovell, Maxwell P. Lee, William R. Markesbery, Guo Min Li, Liya Gu

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

Patients with Alzheimer's disease (AD) exhibit higher levels of 8-oxo-guanine (8-oxoG) DNA lesions in their brain, suggesting a reduced or defective 8-oxoG repair. To test this hypothesis, this study investigated 14 AD patients and 10 age-matched controls for mutations of the major 8-oxoG removal gene OGG1. Whereas no alterations were detected in any control samples, four AD patients exhibited mutations in OGG1, two carried a common single base (C796) deletion that alters the carboxyl terminal sequence of OGG1, and the other two had nucleotide alterations leading to single amino acid substitutions. In vitro biochemical assays revealed that the protein encoded by the C796-deleted OGG1 completely lost its 8-oxoG glycosylase activity, and that the two single residue-substituted OGG1 proteins showed a significant reduction in the glycosylase activity. These results were consistent with the fact that nuclear extracts derived from a limited number of AD patients with OGG1 mutations exhibited greatly reduced 8-oxoG glycosylase activity compared with age-matched controls and AD patients without OGG1 alterations. Our findings suggest that defects in OGG1 may be important in the pathogenesis of AD in a significant fraction of AD patients and provide new insight into the molecular basis for the disease.

Original languageEnglish
Pages (from-to)2759-2766
Number of pages8
JournalNucleic Acids Research
Volume35
Issue number8
DOIs
StatePublished - Apr 1 2007
Externally publishedYes

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Guanine
Alzheimer Disease
Mutation
Amino Acid Substitution
Proteins
Nucleotides
DNA
Brain
Genes

ASJC Scopus subject areas

  • Genetics

Cite this

Identification and characterization of OGG1 mutations in patients with Alzheimer's disease. / Mao, Guogen; Pan, Xiaoyu; Zhu, Bei Bei; Zhang, Yanbin; Yuan, Fenghua; Huang, Jian; Lovell, Mark A.; Lee, Maxwell P.; Markesbery, William R.; Li, Guo Min; Gu, Liya.

In: Nucleic Acids Research, Vol. 35, No. 8, 01.04.2007, p. 2759-2766.

Research output: Contribution to journalArticle

Mao, G, Pan, X, Zhu, BB, Zhang, Y, Yuan, F, Huang, J, Lovell, MA, Lee, MP, Markesbery, WR, Li, GM & Gu, L 2007, 'Identification and characterization of OGG1 mutations in patients with Alzheimer's disease', Nucleic Acids Research, vol. 35, no. 8, pp. 2759-2766. https://doi.org/10.1093/nar/gkm189
Mao, Guogen ; Pan, Xiaoyu ; Zhu, Bei Bei ; Zhang, Yanbin ; Yuan, Fenghua ; Huang, Jian ; Lovell, Mark A. ; Lee, Maxwell P. ; Markesbery, William R. ; Li, Guo Min ; Gu, Liya. / Identification and characterization of OGG1 mutations in patients with Alzheimer's disease. In: Nucleic Acids Research. 2007 ; Vol. 35, No. 8. pp. 2759-2766.
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