title: Identification and characterization of OGG1 mutations in patients with Alzheimer's disease.
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.
authors.affiliation: Graduate Center for Toxicology, University of Kentucky, Lexington, KY, USA.
authors.forename: Guogen
authors.initials: G
authors.lastname: Mao
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Pan
authors.forename: Bei-Bei
authors.initials: BB
authors.lastname: Zhu
authors.forename: Yanbin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Fenghua
authors.initials: F
authors.lastname: Yuan
authors.forename: Jian
authors.initials: J
authors.lastname: Huang
authors.forename: Mark A
authors.initials: MA
authors.lastname: Lovell
authors.forename: Maxwell P
authors.initials: MP
authors.lastname: Lee
authors.forename: William R
authors.initials: WR
authors.lastname: Markesbery
authors.forename: Guo-Min
authors.initials: GM
authors.lastname: Li
authors.forename: Liya
authors.initials: L
authors.lastname: Gu
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics*; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001483:Base Sequence; D001921:Brain / Q000201:enzymology; D045647:DNA Glycosylases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D017354:Point Mutation
chemical_list: D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human