DNA Damage, DNA Repair, Aging, and Neurodegeneration

Maynard, Scott; Fang, Evandro Fei; Scheibye‐Knudsen, Morten; Croteau, Deborah L.; Bohr, Vilhelm A.

doi:10.1101/cshperspect.a025130

Cited by 334 publications

(218 citation statements)

References 168 publications

(200 reference statements)

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“…Progressive damage to nuclear DNA and mitochondrial DNA (mtDNA) is considered to be a prominent contributing factor to the ageing process and may underlie several age-associated diseases 4,20,28,29 . Cells have multiple DNA repair pathways to rectify the myriad types of DNA lesions that occur and to maintain DNA integrity in the nucleus and in mitochondria (BOX 1).…”

Section: Nuclear Dna Repair and Mitochondrial Healthmentioning

confidence: 99%

“…As DNA is constantly assaulted by both endogenous (for example, reactive oxygen species and hydrolysis) and exogenous (such as ultraviolet and ionizing radiation) stresses, cells have evolved several DNA repair pathways to maintain the integrity of DNA 3,4,141–144 . Major DNA repair pathways in the nucleus include direct reversal (DR) of the lesion (usually methylation), base excision repair (BER), mismatch repair (MMR), nucleotide excision repair (NER; comprising global genome NER and transcription-coupled NER), double-strand break repair (DSBR, which includes non-homologous end-joining (NHEJ) and homologous recombination (HR)) and inter-strand crosslink repair (ICLR), among others (see the figure).…”

Section: Nuclear Dna Repair and Mitochondrial Healthmentioning

confidence: 99%

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Nuclear DNA damage signalling to mitochondria in ageing

Fang

Scheibye‐Knudsen

Chua

et al. 2016

Nat Rev Mol Cell Biol

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327

278

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Mitochondrial dysfunction is a hallmark of ageing, and mitochondrial maintenance may lead to increased healthspan. Emerging evidence suggests a crucial role for signalling from the nucleus to mitochondria (NM signalling) in regulating mitochondrial function and ageing. An important initiator of NM signalling is nuclear DNA damage, which accumulates with age and may contribute to the development of age-associated diseases. DNA damage-dependent NM signalling constitutes a network that includes nuclear sirtuins and controls genomic stability and mitochondrial integrity. Pharmacological modulation of NM signalling is a promising novel approach for the prevention and treatment of age-associated diseases.

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Section: Nuclear Dna Repair and Mitochondrial Healthmentioning

confidence: 99%

Section: Nuclear Dna Repair and Mitochondrial Healthmentioning

confidence: 99%

Nuclear DNA damage signalling to mitochondria in ageing

Fang

Scheibye‐Knudsen

Chua

et al. 2016

Nat Rev Mol Cell Biol

Self Cite

327

278

View full text Add to dashboard Cite

show abstract

“…Just like CIN can cause DNA damage that is regarded as a main cause of GIN, it is often difficult to dissect causes and consequences of various forms of GIN. Accumulation of GIN, both at the nucleotide (Maynard et al, 2015) and chromosome level (Ricke and van Deursen, 2013; Yurov et al, 2014), is associated with neurodegenerative diseases (ND). Below we summarize succinctly the main types of GIN, how they are generated, their known correlation with CIN, and how they relate to aging and ND.…”

Section: Gin-cin Complexity: a Two Sided Coinmentioning

confidence: 99%

Mechanisms and consequences of aneuploidy and chromosome instability in the aging brain

Andriani

Vijg

Montagna

2017

Mechanisms of Ageing and Development

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Aneuploidy and polyploidy are a form of Genomic Instability (GIN) known as Chromosomal Instability (CIN) characterized by sporadic abnormalities in chromosome copy numbers. Aneuploidy is commonly linked to pathological states. It is a hallmark of spontaneous abortions and birth defects and it is observed virtually in every human tumor, therefore being generally regarded as detrimental for the development or the maturation of tissues under physiological conditions. Polyploidy however, occurs as part of normal physiological processes during maturation and differentiation of some mammalian cell types. Surprisingly, high levels of aneuploidy are present in the brain, and their frequency increases with age suggesting that the brain is able to maintain its functionality in the presence of high levels of mosaic aneuploidy. Because somatic aneuploidy with age can reach exceptionally high levels, it is likely to have long-term adverse effects in this organ. We describe the mechanisms accountable for an abnormal DNA content with a particular emphasis on the CNS where cell division is limited. Next, we briefly summarize the types of GIN known to date and discuss how they interconnect with CIN. Lastly we highlight how several forms of CIN may contribute to genetic variation, tissue degeneration and disease in the CNS.

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“…DNA damage is known to be associated with neurodegeneration 132,133 , making this mechanism a prime candidate. Furthermore, oxidative stress and mitochondrial dysfunction are known to occur in FXTAS 70,71,134,135 and would increase the likelihood of DNA damage.…”

Section: Molecular Pathogenesis Of Fxtasmentioning

confidence: 99%

Fragile X-associated tremor/ataxia syndrome — features, mechanisms and management

2016

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Many physicians are unaware of the many phenotypes associated with the fragile X premutation, an expansion in the 5' untranslated region of the fragile X mental retardation 1 (FMR1) gene that consists of 55-200 CGG repeats. The most severe of these phenotypes is fragile X-associated tremor/ataxia syndrome (FXTAS), which occurs in the majority of ageing male premutation carriers but in fewer than 20% of ageing women with the premutation. The prevalence of the premutation is 1 in 150-300 females, and 1 in 400-850 males, so physicians are likely to see people affected by FXTAS. Fragile X DNA testing is broadly available in the Western world. The clinical phenotype of FXTAS at presentation can vary and includes intention tremor, cerebellar ataxia, neuropathic pain, memory and/or executive function deficits, parkinsonian features, and psychological disorders, such as depression, anxiety and/or apathy. FXTAS causes brain atrophy and white matter disease, usually in the middle cerebellar peduncles, the periventricular area, and the splenium and/or genu of the corpus callosum. Here, we review the complexities involved in the clinical management of FXTAS and consider how targeted treatment for these clinical features of FXTAS will result from advances in our understanding of the molecular mechanisms that underlie this neurodegenerative disorder. Such targeted approaches should also be more broadly applicable to earlier forms of clinical involvement among premutation carriers.

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DNA Damage, DNA Repair, Aging, and Neurodegeneration

Cited by 334 publications

References 168 publications

Nuclear DNA damage signalling to mitochondria in ageing

Nuclear DNA damage signalling to mitochondria in ageing

Mechanisms and consequences of aneuploidy and chromosome instability in the aging brain

Fragile X-associated tremor/ataxia syndrome — features, mechanisms and management

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