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.
|Number of pages||8|
|Journal||Nucleic Acids Research|
|State||Published - Apr 2007|
Bibliographical noteFunding Information:
We thank Drs Sankar Mitra and Tapas Hazra for the human OGG1 expression vector. This work was supported by a program project grant (P01 AG05119) and an Alzheimer’s Disease Center Grant (1P30 AG0 28383) from the National Institute on Aging. X.P. was supported by a pre-doctoral fellowship from China Scholarship Council. G.M.L. is the James-Gardner Endowed Chair in Cancer Research, and W.R.M. is the Commonwealth Endowed Chair in Aging. Funding to pay the Open Access publication charges for this article was provided by the James F. Madeline and Edith D. Gardner Endowment to G.M.L.
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