Effect of caloric restriction on base-excision repair (BER) in the aging rat brain

Kisby, Glen E.; Kohama, Steven G.; Olivas, Antoinette; Churchwell, Mona I.; Doerge, Daniel R.; Spangler, Edward L.; Cabo, Rafael de; Ingram, Donald K.; Imhof, Barry; Bao, Gaobin

doi:10.1016/j.exger.2009.12.003

Cited by 26 publications

(16 citation statements)

References 46 publications

(57 reference statements)

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“…For example, among the DNA glycosylases, OGG1 expression is decreased during ageing in rat brain [27], whereas NEIL1 and NEIL2 levels are highly increased, consistent with the role of NEILs’ in transcription-associated repair and high transcriptional activity in the brain [26, 28–30]. The activity of APE1 is reduced in the frontal/parietal cortex, cerebellum, brainstem, midbrain and hypothalamus in aged rats [31]. Among DNA polymerases, Polβ is highly and ubiquitously expressed in brain regions [32] while its activity decreases in the brain upon aging [33].…”

Section: Genome Damage and Repair Responses In Central Nervous Systemmentioning

confidence: 79%

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?

Weng

Dharmalingam

Vasquez

et al. 2017

Mechanisms of Ageing and Development

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A foremost challenge for the neurons, which are among the most oxygenated cells, is the genome damage caused by chronic exposure to endogenous reactive oxygen species (ROS), formed as cellular respiratory byproducts. Strong metabolic activity associated with high transcriptional levels in these long lived post-mitotic cells render them vulnerable to oxidative genome damage, including DNA strand breaks and mutagenic base lesions. There is growing evidence for the accumulation of unrepaired DNA lesions in the central nervous system (CNS) during accelerated ageing and progressive neurodegeneration. Several germ line mutations in DNA repair or DNA damage response (DDR) signaling genes are uniquely manifested in the phenotype of neuronal dysfunction and are etiologically linked to many neurodegenerative disorders. Studies in our lab and elsewhere revealed that pro-oxidant metals, ROS and misfolded amyloidogenic proteins not only contribute to genome damage in CNS, but also impede their repair/DDR signaling leading to persistent damage accumulation, a common feature in sporadic neurodegeneration. Here, we have reviewed recent advances in our understanding of the etiological implications of DNA damage vs. repair imbalance, abnormal DDR signaling in triggering neurodegeneration and potential of DDR as a target for the amelioration of neurodegenerative diseases.

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Section: Genome Damage and Repair Responses In Central Nervous Systemmentioning

confidence: 79%

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?

Weng

Dharmalingam

Vasquez

et al. 2017

Mechanisms of Ageing and Development

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“…The increased ability to repair oxidative DNA base damage probably accounts for the attenuation of neuronal cell death observed in the ischemically preconditioned rat brains after reperfusion and consequent oxidative stress. In aged rats the activity of APE, the major enzyme responsible for incision of the DNA backbone in BER, is reduced in the frontal/parietal cortex, cerebellum, brainstem, midbrain and hypothalamus compared to young rats (Kisby et al, 2010). While APE activity declined with age, there was no change in the protein levels of APE, Pol β and LIG3 in the rat frontal/parietal cortex perhaps suggesting that the reduced APE activity could be due to altered post-translational modification.…”

Section: Base Excision Repair Deficiencymentioning

confidence: 99%

DNA repair deficiency in neurodegeneration

Jeppesen

Bohr

Stevnsner

2011

Progress in Neurobiology

289

268

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Deficiency in repair of nuclear and mitochondrial DNA damage has been linked to several neurodegenerative disorders. Many recent experimental results indicate that the post-mitotic neurons are particularly prone to accumulation of unrepaired DNA lesions potentially leading to progressive neurodegeneration. Nucleotide excision repair is the cellular pathway responsible for removing helix-distorting DNA damage and deficiency in such repair is found in a number of diseases with neurodegenerative phenotypes, including Xeroderma Pigmentosum and Cockayne syndrome. The main pathway for repairing oxidative base lesions is base excision repair, and such repair is crucial for neurons given their high rates of oxygen metabolism. Mismatch repair corrects base mispairs generated during replication and evidence indicates that oxidative DNA damage can cause this pathway to expand trinucleotide repeats, thereby causing Huntington’s disease. Single-strand breaks are common DNA lesions and are associated with the neurodegenerative diseases, ataxia-oculomotor apraxia-1 and spinocerebellar ataxia with axonal neuropathy-1. DNA double-strand breaks are toxic lesions and two main pathways exist for their repair: homologous recombination and non-homologous end-joining. Ataxia telangiectasia and related disorders with defects in these pathways illustrate that such defects can lead to early childhood neurodegeneration. Aging is a risk factor for neurodegeneration and accumulation of oxidative mitochondrial DNA damage may be linked with the age-associated neurodegenerative disorders Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. Mutation in the WRN protein leads to the premature aging disease Werner syndrome, a disorder that features neurodegeneration. In this article we review the evidence linking deficiencies in the DNA repair pathways with neurodegeneration.

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“…Multiple enzymes of the plasma membrane redox system, which function to suppress oxidative stress (NADH-quinone oxidoreductase 1, NADH-ferrocyanide reductase, NADH-ascorbate free radical reductase, NADH-coenzyme Q10 reductase, and NADH-cytochrome c reductase), are up-regulated in brain cells in response to ER (Hyun et al, 2006). The usual age-related decline in the level of the DNA base excision repair enzyme APE1 is attenuated in the brains of rats maintained on an ER diet (Kisby et al, 2010). ER can also up-regulate autophagy which can enhance the removal of damaged proteins, membranes and organelles (Alirezaei et al, 2010).…”

Section: Energy Restriction and Exercise Activate Adaptive Stress Resmentioning

confidence: 99%

Energy Intake and Exercise as Determinants of Brain Health and Vulnerability to Injury and Disease

2012

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Evolution favored individuals with superior cognitive and physical abilities under conditions of limited food sources, and brain function can therefore be optimized by intermittent dietary energy restriction (ER) and exercise. Such energetic challenges engage adaptive cellular stress response signaling pathways in neurons involving neurotrophic factors, protein chaperones, DNA repair proteins, autophagy and mitochondrial biogenesis. By suppressing adaptive cellular stress responses, overeating and a sedentary lifestyle may increase the risk of Alzheimer’s and Parkinson’s diseases, stroke, and depression. Intense concerted efforts of governments, families, schools and physicians will be required to successfully implement brain-healthy lifestyles that incorporate ER and exercise.

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Effect of caloric restriction on base-excision repair (BER) in the aging rat brain

Cited by 26 publications

References 46 publications

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?

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?

DNA repair deficiency in neurodegeneration

Energy Intake and Exercise as Determinants of Brain Health and Vulnerability to Injury and Disease

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