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

doi:10.1093/nar/gkm189

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

Journal article

Open access

Peer reviewed

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, …

Nucleic acids research, Vol.35(8), pp.2759-2766

2007-04

DOI: https://doi.org/10.1093/nar/gkm189

PMCID: PMC1885677

PMID: 17426120

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.

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.152 Molecular & Cell Biology - DNA Damage; 1.152.251 Nucleotide Excision Repair
Web Of Science research areas: Biochemistry & Molecular Biology
ESI research areas: Biology & Biochemistry

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Title: Identification and characterization of OGG1 mutations in patients with Alzheimer's disease
Creators: Guogen Mao - 1Graduate Center for Toxicology, 2Department of Pathology & Laboratory Medicine, 3Sanders-Brown Center on Aging, 4Department of Chemistry, University of Kentucky, Lexington, KY, USA, 5College of Life Sciences, Wuhan University, Wuhan, China and 6Laboratory of Population Genetics, National Cancer Institute, Bethesda, MD, USA
Xiaoyu Pan - 1Graduate Center for Toxicology, 2Department of Pathology & Laboratory Medicine, 3Sanders-Brown Center on Aging, 4Department of Chemistry, University of Kentucky, Lexington, KY, USA, 5College of Life Sciences, Wuhan University, Wuhan, China and 6Laboratory of Population Genetics, National Cancer Institute, Bethesda, MD, USA
Bei-Bei Zhu - 1Graduate Center for Toxicology, 2Department of Pathology & Laboratory Medicine, 3Sanders-Brown Center on Aging, 4Department of Chemistry, University of Kentucky, Lexington, KY, USA, 5College of Life Sciences, Wuhan University, Wuhan, China and 6Laboratory of Population Genetics, National Cancer Institute, Bethesda, MD, USA
Yanbin Zhang - 1Graduate Center for Toxicology, 2Department of Pathology & Laboratory Medicine, 3Sanders-Brown Center on Aging, 4Department of Chemistry, University of Kentucky, Lexington, KY, USA, 5College of Life Sciences, Wuhan University, Wuhan, China and 6Laboratory of Population Genetics, National Cancer Institute, Bethesda, MD, USA
Fenghua Yuan - 1Graduate Center for Toxicology, 2Department of Pathology & Laboratory Medicine, 3Sanders-Brown Center on Aging, 4Department of Chemistry, University of Kentucky, Lexington, KY, USA, 5College of Life Sciences, Wuhan University, Wuhan, China and 6Laboratory of Population Genetics, National Cancer Institute, Bethesda, MD, USA
Jian Huang - 1Graduate Center for Toxicology, 2Department of Pathology & Laboratory Medicine, 3Sanders-Brown Center on Aging, 4Department of Chemistry, University of Kentucky, Lexington, KY, USA, 5College of Life Sciences, Wuhan University, Wuhan, China and 6Laboratory of Population Genetics, National Cancer Institute, Bethesda, MD, USA
Mark A Lovell - 1Graduate Center for Toxicology, 2Department of Pathology & Laboratory Medicine, 3Sanders-Brown Center on Aging, 4Department of Chemistry, University of Kentucky, Lexington, KY, USA, 5College of Life Sciences, Wuhan University, Wuhan, China and 6Laboratory of Population Genetics, National Cancer Institute, Bethesda, MD, USA
Maxwell P Lee - 1Graduate Center for Toxicology, 2Department of Pathology & Laboratory Medicine, 3Sanders-Brown Center on Aging, 4Department of Chemistry, University of Kentucky, Lexington, KY, USA, 5College of Life Sciences, Wuhan University, Wuhan, China and 6Laboratory of Population Genetics, National Cancer Institute, Bethesda, MD, USA
William R Markesbery - 1Graduate Center for Toxicology, 2Department of Pathology & Laboratory Medicine, 3Sanders-Brown Center on Aging, 4Department of Chemistry, University of Kentucky, Lexington, KY, USA, 5College of Life Sciences, Wuhan University, Wuhan, China and 6Laboratory of Population Genetics, National Cancer Institute, Bethesda, MD, USA
Guo-Min Li - 1Graduate Center for Toxicology, 2Department of Pathology & Laboratory Medicine, 3Sanders-Brown Center on Aging, 4Department of Chemistry, University of Kentucky, Lexington, KY, USA, 5College of Life Sciences, Wuhan University, Wuhan, China and 6Laboratory of Population Genetics, National Cancer Institute, Bethesda, MD, USA
Liya Gu - 1Graduate Center for Toxicology, 2Department of Pathology & Laboratory Medicine, 3Sanders-Brown Center on Aging, 4Department of Chemistry, University of Kentucky, Lexington, KY, USA, 5College of Life Sciences, Wuhan University, Wuhan, China and 6Laboratory of Population Genetics, National Cancer Institute, Bethesda, MD, USA
Publication Details: Nucleic acids research, Vol.35(8), pp.2759-2766
Publisher: Oxford University Press
Academic Unit: Miller School of Medicine; Biochemistry & Molecular Biology Research; UMMG Dept of Pediatrics - Neonatology
Language: English
Resource Type: Journal article
PMID: 17426120
PMCID: PMC1885677
Record Identifier: 991031561645202976