Base excision DNA repair levels in mitochondrial lysates of Alzheimer's disease

Abstract

Alzheimer’s disease (AD) is a senile dementia with increased incidence in older subjects (age>65 years). One of the earliest markers of AD is oxidative DNA damage. Recently it has been reported that preclinical AD patient brains show elevated levels of oxidative damage in both nuclear and mitochondrial nucleic acids. Moreover, different oxidative lesions in mitochondrial DNA are between 5–10-fold higher than in nuclear DNA in both control and AD postmortem brains. We previously showed that there is a significant loss of base excision repair (BER) components in whole tissue extracts of AD and mild cognitive impairment subjects relative to matched control subjects. However, comprehensive analysis of specific steps in base excision repair levels in mitochondrial extracts of AD patient brains is not available. In this study we mainly investigated various components of BER in mitochondrial extracts of AD and matched control postmortem brain samples. We found that the 5-hydroxyuracil (5OHU) incision and ligase activities are significantly lower in AD brains whereas the uracil incision, abasic site cleavage and dNTP incorporation activities are normal in these samples.

The role of DNA base excision repair in brain homeostasis and disease

“…5-hydroxyuracil (5OHU) incision and DNA ligation activities were significantly reduced in mitochondrial lysates from AD brains [87]. In the same samples, the concentration of NEIL1 DNA glycosylase was much lower than in the control samples [87]. Together, these results support the idea that increased mtDNA damage together with a reduction of mtBER play a role in AD pathology [82, 89].…”

“…If one proposes to study quantify or characterize specific BER enzyme functions in post-mortem brain, the amount of tissue available can be prohibitively small. For example, it is a big challenge to get enough and highly purified material to study mtBER activity in postmortem brain tissue [87]. Alternative approaches could include future use of induced pluripotent stem cells (iPSCs), where such cells could even carry putative AD susceptibility alleles.…”

“…Mitochondrial dysfunction and increased mtDNA damage have been reported frequently in AD brains [89–91]. 5-hydroxyuracil (5OHU) incision and DNA ligation activities were significantly reduced in mitochondrial lysates from AD brains [87]. In the same samples, the concentration of NEIL1 DNA glycosylase was much lower than in the control samples [87].…”

DNA Damage, DNA Repair, Aging, and Neurodegeneration

“…LIGIII is the only ligase essential for life and it is also a component of the mtDNA replication and DNA repair machinery (Tomkinson et al 2013). Reduced levels and activity of LIGIII have been detected in major human neurodegenerative diseases including ataxia telangiectasia (in ATM patient cells and ATM-KO mice) (Sharma et al 2014) and Alzheimer’s disease (Canugovi et al 2013, 2014). LIGIII activity has been reported to be the rate-limiting step of BER in mitochondria (Akbari et al 2014).…”

Genome instability in Alzheimer disease

“…Increased DNA oxidation was reported in post mortem brains of humans with AD (Bradley-Whitman et al, 2014; Butterfield et al, 2001; Finkel and Holbrook, 2000; Gabbita et al, 1998; Lovell et al, 1999; Lovell and Markesbery, 2007a; Markesbery and Lovell, 2006; Wang et al, 2005), mild cognitive impairment (MCI) (Lovell and Markesbery, 2007b; Wang et al, 2006) and preclinical AD (Lovell et al, 2011). It was also observed in many studies that DNA repair is dysregulated in AD (Bucholtz and Demuth, 2013; Canugovi et al, 2014; Forestier et al, 2012; Leandro et al, 2013; Pinto et al, 2013; Weissman et al, 2007; Wu et al, 2014). These findings suggest that oxidative DNA damage and less than optimal DNA repair may play a potential role in the pathogenesis of AD.…”