DNA repair, mitochondria, and neurodegeneration

doi:10.1016/j.neuroscience.2006.08.061

Neuroscience

Volume 145, Issue 4, 14 April 2007, Pages 1318-1329

https://doi.org/10.1016/j.neuroscience.2006.08.061 Get rights and content

Abstract

Accumulation of nuclear and mitochondrial DNA damage is thought to be particularly deleterious in post-mitotic cells, which cannot be replaced through cell division. Recent experimental evidence demonstrates the importance of DNA damage responses for neuronal survival. Here, we summarize current literature on DNA damage responses in the mammalian CNS in aging and neurodegeneration. Base excision repair (BER) is the main pathway for the removal of small DNA base modifications, such as alkylation, deamination and oxidation, which are generated as by-products of normal metabolism and accumulate with age in various experimental models. Using neuronal cell cultures, human brain tissue and animal models, we and others have shown an active BER pathway functioning in the brain, both in the mitochondrial and nuclear compartments. Mitochondrial DNA repair may play a more essential role in neuronal cells because these cells depend largely on intact mitochondrial function for energy metabolism. We have characterized several BER enzymes in mammalian mitochondria and have shown that BER activities change with age in mitochondria from different brain regions. Together, the results reviewed here advocate that mitochondrial DNA damage response plays an important role in aging and in the pathogenesis of neurodegenerative diseases.

Section snippets

The mechanisms of nDNA and mtDNA BER

BER is the main pathway to repair small DNA modifications caused by alkylation, deamination and oxidation. The first step in BER is the removal of the damaged base by substrate-specific DNA glycosylases. These enzymes catalyze the hydrolysis of the N-glycosidic bond between the modified base and the sugar moiety to release the base and generate an abasic site. The abasic (AP) site, which can also be generated spontaneously or by radiation and chemicals, is then cleaved by an AP lyase or AP

DNA damage and repair in the aging CNS

ROS are continuously formed as consequence of normal cellular metabolism and in response to environmental factors such as UV light, ionizing radiation, heat, and pollution. The mammalian brain is considered particularly vulnerable to the deleterious effects of ROS due to its high oxygen consumption, and thus it is hypothesized that chronic exposure to ROS results in oxidative damage to cellular components, leading to the progressive neuronal loss associated with aging and neurodegeneration (

AD is a progressive age-dependent neurodegenerative disorder that is the most common cause of dementia in people over the age of 65. The prevalence of AD is currently estimated at 1.47% or 4 million people in the USA, compared with 0.37% or 1 million people with PD. The main pathological hallmarks of the disease are loss of neuronal subpopulations, intracellular neurofibrillary tangles formed by aggregation of hyperphosphorylated tau protein, and extracellular neuritic plaques formed by

PD

PD is a common neurodegenerative disease, affecting 1% of the population over the age of 65. Clinically, it is characterized by bradykinesia, tremor and muscular rigidity. The pathological hallmarks of PD include loss of dopaminergic neurons in the substantia nigra and the formation of inclusion bodies, termed Lewy bodies, composed of an aggregated form of the protein α-synuclein. Several genes that cause the familial (inherited) form of PD, but are also associated with 5–10% of sporadic PD

Huntington’s disease (HD)

HD is an autosomal dominant neurodegenerative disorder characterized by selective loss of striatal projection neurons, leading to motor and cognitive alterations. The genetic basis of this disease is an abnormally expanded and unstable CAG repeat, encoding a polyglutamine tract within the coding region of the HD gene (Myers, 2004). There is evidence that mutant huntingtin protein causes mitochondrial dysfunction including, but not limited to, reduced calcium uptake and membrane depolarization

Amyotrophic lateral sclerosis (ALS)

ALS is a group of fatal motor neuron disorders characterized by adult onset of progressive dysfunction and loss of cortical, brainstem and spinal cord motor neurons. Approximately 10% of ALS cases are inherited and defined as familial amyotrophic lateral sclerosis (FALS) while the majority of cases are sporadic and have no genetic component (SALS). About 20% of FALS cases are associated with dominantly inherited mutations in the Cu/Zn superoxide dismutase protein (SOD1) (Bruijn et al., 2004).

Other neurodegenerative disorders

Several other human disorders caused by genetic defects in DNA damage response or repair show premature aging and neurodegeneration, strengthening the hypothesis that these events are associated (Rolig and McKinnon, 2000). Among these are ataxia telangiectasia (Barzilai et al., 2002), Werner (Bohr, 2005), Bloom (Cheok et al., 2005), Rothmund-Thomson (Mohaghegh and Hickson, 2002) and Cockayne syndromes (CS) (Licht et al., 2003). Advances in our understanding of these disorders may provide

Conclusion

The findings discussed above greatly emphasize the importance of DNA damage responses in the mammalian CNS during aging and neurodegeneration. Accumulation of nDNA and mtDNA base modifications has been identified as a major contributing factor to genomic instability and mitochondrial dysfunctions in normal aging as well as in age-related neurodegenerative disorders such as AD, PD, HD and ALS. The studies reviewed here implicate BER as an essential repair mechanism for the proper maintenance of

Acknowledgments

This research was supported (in part) by the Intramural Research Program of the NIH, National Institute on Aging.

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AgingDNA repair, mitochondria, and neurodegeneration

Abstract

Section snippets

The mechanisms of nDNA and mtDNA BER

DNA damage and repair in the aging CNS

AD

PD

Huntington’s disease (HD)

Amyotrophic lateral sclerosis (ALS)

Other neurodegenerative disorders

Conclusion

Acknowledgments

Trends Neurosci

DNA Repair (Amst)

Free Radic Biol Med

Mutat Res

Neurobiol Aging

Lab Invest

J Biol Chem

Biochem Pharmacol

Mutat Res

Brain Res

J Biol Chem

J Biol Chem

Neurobiol Aging

Brain Res Mol Brain Res

Mutat Res

J Biol Chem

J Biol Chem

Biochem Biophys Res Commun

Am J Hum Genet

Mutat Res

Brain Res

J Biol Chem

Ageing Res Rev

Trends Neurosci

Int J Hyg Environ Health

Int J Biochem Cell Biol

Neurobiol Aging

Lancet

Neurobiol Aging

NeuroRx

Life Sci

Lab Invest

Beta-amyloid peptides induce mitochondrial dysfunction and oxidative stress in astrocytes and death of neurons through activation of NADPH oxidase

J Neurosci

Increased oxidative damage to DNA in an animal model of amyotrophic lateral sclerosis

Free Radic Res

No evidence for increased oxidative damage to lipids, proteins, or DNA in Huntington’s disease

J Neurochem

Oxidants, antioxidants, and the degenerative diseases of aging

Proc Natl Acad Sci U S A

Radiosensitivity in Huntington’s-chorea cell strains: possible pre-clinical diagnosis

Heredity

Aging in vertebrates, and the effect of caloric restriction: a mitochondrial free radical production-DNA damage mechanism?

Biol Rev Camb Philos Soc

Oxidative damage to mitochondrial DNA is inversely related to maximum life span in the heart and brain of mammals

FASEB J

Mitochondria take center stage in aging and neurodegeneration

Ann Neurol

Chronic systemic pesticide exposure reproduces features of Parkinson’s disease

Nat Neurosci

Increased oxidative damage to DNA in a transgenic mouse model of Huntington’s disease

J Neurochem

DJ-1(PARK7), a novel gene for autosomal recessive, early onset parkinsonism

Neurol Sci

Unraveling the mechanisms involved in motor neuron degeneration in ALS

Annu Rev Neurosci

The Parkinson’s disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization

Proc Natl Acad Sci U S A

Oxidative DNA damage in the aging mouse brain

Mov Disord

Mitochondrial Abeta: a potential focal point for neuronal metabolic dysfunction in Alzheimer’s disease

FASEB J

Age-dependent decline of DNA repair activity for oxidative lesions in rat brain mitochondria

J Neurochem

Roles of the Bloom’s syndrome helicase in the maintenance of genome stability

Biochem Soc Trans

Alzheimer’s brains harbor somatic mtDNA control-region mutations that suppress mitochondrial transcription and replication

Proc Natl Acad Sci U S A

Aging
DNA repair, mitochondria, and neurodegeneration