Alzheimer's disease-associated polymorphisms in human OGG1 alter catalytic activity and sensitize cells to DNA damage

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 characterized the A53T and A288V polymorphic variants and detected a significant reduction in the catalytic activity for both proteins in vitro and in cells. Additionally, the A53T polymorphism has decreased substrate binding, while the A288V polymorphism has reduced AP lyase activity. Both variants have decreased binding to known OGG1 binding partners PARP-1 and XRCC1. We found that OGG1−/− 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 be related to the increase in oxidative damage to DNA found in AD brains.

Chronic oxidative damage together with genome repair deficiency in the neurons is a double whammy for neurodegeneration: Is damage response signaling a potential therapeutic target?

“…General reduction in DNA repair capacity during ageing and in sporadic NDDs could involve multiple mechanisms including, (i) altered transcriptional regulation causing reduced expression of a repair protein (e.g., reduced levels of MRN, DNA-PKcs [143, 163] in CS; reduced OGG1 (in mitochondria) [164] and Polβ in AD [165], reduced breast cancer associated gene 1 (BRCA1) in AD brain [166]); (ii) inhibition of catalytic activity of repair proteins, whose levels are otherwise comparable to healthy neurons in the CNS, primarily by NDD-linked etiological factors like exposure to excessive pro-oxidant metals and ROS (e.g., metal and ROS-mediated inhibition of NEIL1, NEIL2, LigIII, APE1 etc., in AD and PD [167, 168]; reduced catalytic activity of OGG1 in AD [136, 169] and reduced Polβ activity in AD [136, 165] and (iii) abnormal degradation and/or mis-localization of repair proteins (e.g., degradation of ATM and PARP1 by caspases/Matrix-Metallo-Proteinases (MMPs) [170], nuclear to cytoplasmic mis-localization of FUS in ALS [13]. Most of the NDDs have complex etiologies including oxidative stress, pro-oxidant metal and other toxic free radicals, and the misfolded/aggregating protein response, together with extensive accumulation of various types of DNA damages [18].…”

Dietary Antioxidant Intake and Its Association With Cognitive Function in an Ethnically Diverse Sample of US Adults

“…The exposure of ROS has been shown to result in oxidative modification of DNA in brain tissue that in some cases has been shown to accumulate due to reductions of DNA repair. (7–9) Oxidative stress among AD patients is marked by increased antioxidant brain levels, acting as free radical scavengers. (10) In vitro studies suggest that exogenous antioxidants may reduce β-amyloids toxicity in AD patients’ brains (10–12).…”

Genome instability in Alzheimer disease

“…Studies found no significant associations between the Ser326Cys polymorphism in OGG1 and AD (Coppede et al, 2007; Dorszewska et al, 2009; Parildar-Karpuzoglu et al, 2008), although there are some reports on OGG1 mutations (A53T and A288V) in AD patients (Jacob et al, 2013; Mao et al, 2007). MUTYH, an adenine DNA glycosylase that removes adenine opposite 8-oxodG base pairs (Oka and Nakabeppu, 2011), has also been evaluated and no significant associations between MUTYH and late-onset AD risk identified (Kwiatkowski et al, 2015).…”