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.

journal_name

Nucleic Acids Res

journal_title

Nucleic acids research

authors

Mao G,Pan X,Zhu BB,Zhang Y,Yuan F,Huang J,Lovell MA,Lee MP,Markesbery WR,Li GM,Gu L

doi

10.1093/nar/gkm189

subject

Has Abstract

pub_date

2007-01-01 00:00:00

pages

2759-66

issue

8

eissn

0305-1048

issn

1362-4962

pii

gkm189

journal_volume

35

pub_type

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