Alzheimer’s Disease associated polymorphisms in human OGG1 alter catalytic activity and sensitize cells to DNA damage.

Thursday, October 11, 2012 — Poster Session IV
2:00 p.m. – 4:00 p.m.	Natcher Conference Center, Building 45	NIA	OXIDSTRESS-2

* FARE Award Winner

Authors

• KD Jacob
• N Noren Hooten
• A Lohani
• J Barnes
• MK Evans

Abstract

Brain tissues from Alzheimer’s Disease (AD) patients show increased levels of oxidative DNA damage and 7,8-dihydro-8-oxoguanine (8-oxoG) accumulation. In humans, the base excision repair protein 8-oxoguanine-DNA glycosylase (OGG1) is the major enzyme that recognizes and excises the mutagenic DNA base lesion 8-oxoG. Recently, two polymorphisms of OGG1, A53T and A288V, have been identified in brain tissues of AD patients, but little is known about how these polymorphisms may contribute to AD. We have characterized the A53T and A288T polymorphic variants using purified proteins, and detected a 55-75% reduction in the catalytic activity for both proteins and found the A53T polymorphism had significantly decreased substrate binding. We observed both variants have decreased binding to known OGG1 binding partners PARP-1 and XRCC1. In vivo we found that OGG1-/- mouse embryo fibroblast cells expressing A53T and A288V OGG1 were significantly more sensitive to DNA damage and had significantly decreased survival. Our results provide both biochemical and cellular evidence that A53T and A288V polymorphic proteins have deficiencies in catalytic and protein binding activities that could explain the increase in oxidative damage to DNA found in AD brains. These data suggest that OGG1 and these polymorphisms may have a role in AD susceptibility.

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