DNA polymerase β deficiency leads to neurodegeneration and exacerbates Alzheimer disease phenotypes

Sýkora, Peter; Misiak, Magdalena; Wang, Yue; Ghosh, Somnath; Leandro, Giovana da Silva; Liu, Dong; Tian, Jane; Baptiste, Beverly A.; Cong, Wei; Brenerman, Boris; Fang, Evandro Fei; Becker, Kevin G.; Hamilton, Royce J.; Chigurupati, Soumya; Zhang, Yongqing; Egan, Josephine M.; Croteau, Deborah L.; Wilson, David M.; Mattson, Mark P.; Bohr, Vilhelm A.

doi:10.1093/nar/gku1356

Cited by 123 publications

(148 citation statements)

References 106 publications

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“…Mice with Pol␤ heterozygosity have defects in mitochondrion-related pathways in the brain, including oxidative phosphorylation (25). Further, using large-scale mitochondrial extracts from bovine heart, a Pol␤-like activity has been reported (23).…”

Section: Resultsmentioning

confidence: 98%

“…For this experiment, we used brain tissue extracts from Pol␤ heterozygous (HT) mice. Pol␤ HT mice have accelerated age-related neurodegeneration, suggesting that the brain may be selectively affected by Pol␤ heterozygosity (25). WT mitochondrial samples (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…However, Pol␤ HT mice are viable but have altered life span characteristics (36) and elevated carcinogenic risk (37). We have previously extensively characterized the Pol␤ HT mouse and observed a range of differences, particularly in aged mice, that are reflective of an animal with mitochondrial dysfunction (25). Pol␤ HT mice have accelerated neurodegenerative decline and metabolic dysfunction, including an altered respiratory exchange rate (RER) (Fig.…”

Section: Resultsmentioning

confidence: 99%

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DNA Polymerase Beta Participates in Mitochondrial DNA Repair

Sýkora

Kanno

Akbari

et al. 2017

Molecular and Cellular Biology

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We have detected DNA polymerase beta (Pol␤), known as a key nuclear base excision repair (BER) protein, in mitochondrial protein extracts derived from mammalian tissue and cells. Manipulation of the N-terminal sequence affected the amount of Pol␤ in the mitochondria. Using Pol␤ fragments, mitochondrion-specific protein partners were identified, with the interactors functioning mainly in DNA maintenance and mitochondrial import. Of particular interest was the identification of the proteins TWINKLE, SSBP1, and TFAM, all of which are mitochondrion-specific DNA effectors and are known to function in the nucleoid. Pol␤ directly interacted functionally with the mitochondrial helicase TWINKLE. Human kidney cells with Pol␤ knockout (KO) had higher endogenous mitochondrial DNA (mtDNA) damage. Mitochondrial extracts derived from heterozygous Pol␤ mouse tissue and KO cells had lower nucleotide incorporation activity. Mouse-derived Pol␤ null fibroblasts had severely affected metabolic parameters. Indeed, gene knockout of Pol␤ caused mitochondrial dysfunction, including reduced membrane potential and mitochondrial content. We show that Pol␤ is a mitochondrial polymerase involved in mtDNA maintenance and is required for mitochondrial homeostasis.KEYWORDS DNA polymerase beta, mitochondrial DNA repair, TFAM, base excision repair, mitochondria, mitochondrial health, mutational studies C ellular DNA repair is critical for genomic stability, and the accumulation of DNA damage has been linked to many debilitating human disorders, including accelerated aging, cancer, and neurodegeneration (reviewed in references 1 and 2). Mammalian cells have two genomes, nuclear and mitochondrial, and both have the ability to replicate, accumulate DNA damage, and propagate mutations. The nucleus contains the vast majority of the mammalian genome and has extensive ability to repair complex bulky adducts, double-strand breaks (DSB), single-strand breaks (SSB), and hundreds of chemical DNA modifications. The ability to effectively repair this breadth of damage is achieved through multiple, often overlapping, DNA repair pathways. In contrast, the repair of mitochondrial DNA (mtDNA) is a more limited version of nuclear DNA (nDNA) repair. Mitochondria lack nucleotide excision repair, and the presence of double-strand break repair is debated (recently reviewed in reference 3). Despite the mitochondria having attenuated DNA repair capabilities compared to the nucleus, the accumulation of mtDNA damage is not without consequence. Ineffective mtDNA maintenance is the underlying cause of many human diseases, including Alpers syndrome and chronic progressive external ophthalmoplegia (CPEO) caused by mutations in mitochondrial polymerase gamma (Pol␥) or the TWINKLE helicase (4-6). The accu-

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Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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DNA Polymerase Beta Participates in Mitochondrial DNA Repair

Sýkora

Kanno

Akbari

et al. 2017

Molecular and Cellular Biology

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“…Exhaustive research is undergoing in this field but still the enigma behind such progressive neuronal death is not well understood. Over the last several decades the studies have showed that the progression of neurodegenerative diseases involve the decreased antioxidant levels, impaired mitochondrial activity, increased oxidative damage protein, lipid peroxidation, protein modification, DNA damage and apoptosis [4][5][6][7][8][9] . Oxidative protein modifications occur at a low and persistent level in diverse cells and tissues and accumulate in aging and neurodegenerative diseases [10][11][12][13][14][15][16][17][18][19] .…”

Section: Reviewmentioning

confidence: 99%

Antioxidants as a preventive therapeutic option for age related neurodegenerative diseases

Singh

2015

Ther Targets Neurol Dis

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Neurodegenerative diseases: an overview -Neurodegenerative disease term illustrate a range of conditions in which primarily neurons get affected or die. Neurons are the building blocks of the central and peripheral nervous system. Neurons could not reproduce or replace themselves with age therefore, when they get damaged or die they cannot be replaced and lead to specific neurodegenerative disease. Few evidences for the presence of stem cells are reported [1] but still it is not understood whether damaged neuron could regenerate or not. The Parkinson's, Alzheimer's, and Huntington's diseases are the most prevalent age related neurodegenerative diseases of central nervous system involving death of specific neuronal population. The treatment of these neurodegenerative diseases might involve the re-supplementation of specific neuronal population with the help of stem cells but researchers and clinicians did not get noticeable success in this approach yet. Millions of people each year are getting affected by these neurodegenerative diseases and the incidences are increasing further significantly with the extended life expectancy. It has been reported by World Health Organisation (2006) that the number of older people of more than 65 years age are expected to increase to approximately 1 billion in 2030 worldwide. Developing countries like India and China will see the largest increase in numbers of aged persons. Therefore the percentage of aged population in developing countries would increase from 59% to 71% worldwide [2] . Since occurrence of most of the neurodegenerative Advances in our understanding for neurodegenerative mechanisms have increased significantly in last few decades. But still no novel disease modifying therapy has been developed which could prevent the disease progression and drawn our attention towards the development of new alternative therapy. The major obstacle for the development of disease therapy is incomplete knowledge about neurodegenerative mechanisms. Due to the insufficient information about neurodegenerative mechanisms no standard diagnostic tests for the detection of neurodegenerative disease could be develop to date, causes delayed diagnosis and disease worsening. So far the exploratory reports and clinical data have suggested the involvement of oxidative stress, mitochondrial impairment and apoptosis as major neurodegenerative mechanisms. Investigations have elicited that once initiated the degeneration of neurons could not be arrested therefore in the scarcity of curative therapy we should approach for the preventive neurodegenerative therapy. Since oxidative stress has noteworthy involvement in neuronal death solely, and in connection to other death pathways therefore, antioxidants as preventive therapeutics might provide beneficial effects in age related neurodegenerative diseases. With this hypothesis in this review we are discussing about the use of antioxidants as a preventive treatment of neurodegenerative diseases. Such therapies may work in the preventive phase or in curati...

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“…Variant alleles of polymorphisms in the genes coding for human apurinic/apyrimidinic endonuclease APE1 (the main nuclease hydrolysing the phosphodiester backbone 5'-from the abasic site generated by BER glycosylases) and the gene coding for XRCC1, the stabilising factor of ligase III (the primary ligase of BER) were identified as predisposing factors for sporadic Parkinson's disease [138]. Deficiency of DNA polymerase beta was reported to accelerate cognitive decline in transgenic mice modelling AD [139].…”

Section: Don't Throw Away Repair It -Capacity To Repair Genotoxic Damentioning

confidence: 99%

APOE4, oxidative stress and decreased repair capacity - a no-brainer. Faulty lipid metabolism and increased levels of oxidative damage may be risk factors in the pathogenesis of late-onset dementia

Nayyar

Chakalova²

2015

Biodiscovery

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Keywords: Late-onset disease, dementia, APOE, mitochondrial DNA, individual repair capacity.Abbreviations: AD -Alzheimer's disease, APOE -apolipoprotein E, ATP -adenosine triphosphate, BER -base excision repair, CAA -cerebral amyloid angiopathy, CNS -central nervous system, FTD -frontotemporal dementia, HD -Huntington's disease, IMT -intimamedia thickness, IRC -individual repair capacity, MCI -mild cognitive impairment, MND -motor neuron disease, NER -nucleotide excision repair, NMDA -N-methyl-D-aspartate, PD -Parkinson's disease, PDAPP -PDGF promoter expressing amyloid precursor protein, ROS -reactive oxygen species; SOD -superoxide dismutase, VCI -vascular cognitive decline.* Corresponding Authors: Ashima Nayyar, email: a.nayyar@abertay.ac.uk Conflict of Interests:No potential conflict of interest was disclosed by any of the authors. AbstractDementia is very common in the elderly and its incidence increases in an age-dependent fashion. Alzheimer's disease and vascular cognitive decline are the most common cases of dementia in the elderly. Amyloid burden and increased levels of oxidative damage have been implicated to play significant roles in the pathogenesis of late-onset dementia. In this paper we propose that there are three major genetic factors that may modulate the risk for dementia in later life: carriership of APOE variant alleles, carriership of mitochondrial DNA of haplogroups associated with ineffective oxygen utilisation (specifically, haplogroup H) and carriership of genetic polymorphisms conferring subtly deficient DNA repair. All three factors are quite common in the European populations. Each of these three factors may not have significant effect on the phenotype when taken separately, but when combined in the same genotype, the effects may be cumulative. Further studies are needed in order to elucidate the genotype-phenotype relationships and provide a reliable basis for assessment of the genetic risk for sporadic late-onset dementia. Lifestyle alterations and therapies targeted at decreasing the oxidative burden to aging cells and tissues may decrease the risk for neurological decline in later life.

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DNA polymerase β deficiency leads to neurodegeneration and exacerbates Alzheimer disease phenotypes

Cited by 123 publications

References 106 publications

DNA Polymerase Beta Participates in Mitochondrial DNA Repair

DNA Polymerase Beta Participates in Mitochondrial DNA Repair

Antioxidants as a preventive therapeutic option for age related neurodegenerative diseases

APOE4, oxidative stress and decreased repair capacity - a no-brainer. Faulty lipid metabolism and increased levels of oxidative damage may be risk factors in the pathogenesis of late-onset dementia

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