Chromosome Instability in the Neurodegenerating Brain

Yurov, Yuri B.; Vorsanova, Svetlana G.; Iourov, Ivan Y.

doi:10.3389/fgene.2019.00892

Cited by 36 publications

(39 citation statements)

References 36 publications

(146 reference statements)

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“…Brain has a high level of aneuploidy and the frequency increases with aging [206]. CIN is associated with neurodegeneration [207]. X chromosome aneuploidy is associated with AD [207,208].…”

Section: Contributions Of Chromosome Instability To Admentioning

confidence: 99%

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Contributions of DNA Damage to Alzheimer’s Disease

Lin

Kapoor

et al. 2020

IJMS

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Alzheimer's disease (AD) is the most common type of neurodegenerative disease. Its typical pathology consists of extracellular amyloid-β (Aβ) plaques and intracellular tau neurofibrillary tangles. Mutations in the APP, PSEN1, and PSEN2 genes increase Aβ production and aggregation, and thus cause early onset or familial AD. Even with this strong genetic evidence, recent studies support AD to result from complex etiological alterations. Among them, aging is the strongest risk factor for the vast majority of AD cases: Sporadic late onset AD (LOAD). Accumulation of DNA damage is a well-established aging factor. In this regard, a large amount of evidence reveals DNA damage as a critical pathological cause of AD. Clinically, DNA damage is accumulated in brains of AD patients. Genetically, defects in DNA damage repair resulted from mutations in the BRAC1 and other DNA damage repair genes occur in AD brain and facilitate the pathogenesis. Abnormalities in DNA damage repair can be used as diagnostic biomarkers for AD. In this review, we discuss the association, the causative potential, and the biomarker values of DNA damage in AD pathogenesis.Int. J. Mol. Sci. 2020, 21, 1666 2 of 26 amyloid (senile) plaques in AD brain [9][10][11]. Furthermore, CDK5 activities affect DNA damage response [12], supporting a linkage of DNA damage with AD [13,14].Aβ peptides are directly produced by sequential cleavages of APP by βand γ-secretase; the proteolytic c-terminal fragment of APP (CTFβ) of β-secretase is cleaved within the cell membrane by γ-secretase to generate neurotoxic Aβ peptides with length ranging from 38-43 residues [15][16][17][18][19]. The 40 residue Aβ peptide (Aβ 1-40 ) is the major product, accounting for more than 50% of Aβ peptides [9,17]. Although the Aβ 1-42 peptide consists of less than 10% of Aβ peptides [16,17], it is more neurotoxic and associates with a higher risk of AD because of its propensity of aggregation [9]. The importance of Aβ in AD pathogenesis is illustrated by mutations of APP, PSEN1, and PREN2 genes in familial AD with the latter two encoding the presenilin 1 and presenilin 2 subunit of γ-secretase. Individuals with these mutations develop early onset dementia in an autosomal-dominant manner [20]; the typical onset starts between 30 and 50 years of age in PSEN1 mutant carriers with some being affected at in their 20s [20,21]. γ-secretase with mutant presenilin 1 or presenilin 2 subunit favors Aβ 1-42 production [16,17]. These genetic observations led to formation of the amyloid cascade hypothesis, in which abnormal Aβ drives AD pathogenesis via regulating other pathological events including tau pathology [22][23][24][25][26][27]. This hypothesis is supported by the similar pathological features between familial AD and sporadic late onset AD (LOAD) [20]. Although familial AD constitutes less than 1% of AD cases [28,29], the hypothesis has been widely accepted to guide research in advancing the understanding of both familial AD and LOAD in the past two decades [30,31].Nonetheless, it is becoming in...

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“…Brain has a high level of aneuploidy and the frequency increases with aging [206]. CIN is associated with neurodegeneration [207]. X chromosome aneuploidy is associated with AD [207,208].…”

Section: Contributions Of Chromosome Instability To Admentioning

confidence: 99%

“…CIN is associated with neurodegeneration [207]. X chromosome aneuploidy is associated with AD [207,208]. Down syndrome is associated with chromosome 21 trisomy and all DS patients develop AD [145][146][147][148].…”

Section: Contributions Of Chromosome Instability To Admentioning

confidence: 99%

Contributions of DNA Damage to Alzheimer’s Disease

Lin

Kapoor

et al. 2020

IJMS

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“…There is a strong evidence that somatic chromosomal mosaicism and instability contributes to the pathogenesis of brain diseases [21,[41][42][43][44][45]. Chromosomal mosaicism has been systematically observed in autistic individuals [5,7,46,47].…”

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confidence: 99%

“…In schizophrenia, the diseased brain exhibits tissue-specific mosaicism manifested as aneuploidy and specific copy number variations [48][49][50][51][52]. Neurodegeneration has been found to be mediated by somatic aneuploidy and chromosomal instability confined to degenerating brain areas [44,[53][54][55]. More precisely, Alzheimer's disease has been associated with brain-specific genomic/chromosomal instability (e.g.…”

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confidence: 99%

Dynamic nature of somatic chromosomal mosaicism, genetic-environmental interactions and therapeutic opportunities in disease and aging

2020

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Background: Somatic chromosomal mosaicism is the presence of cell populations differing with respect to the chromosome complements (e.g. normal and abnormal) in an individual. Chromosomal mosaicism is associated with a wide spectrum of disease conditions and aging. Studying somatic genome variations has indicated that amounts of chromosomally abnormal cells are likely to be unstable. As a result, dynamic changes of mosaicism rates occur through ontogeny. Additionally, a correlation between disease severity and mosaicism rates appears to exist. High mosaicism rates are usually associated with severe disease phenotypes, whereas low-level mosaicism is generally observed in milder disease phenotypes or in presumably unaffected individuals. Here, we hypothesize that dynamic nature of somatic chromosomal mosaicism may result from genetic-environmental interactions creating therapeutic opportunities in the associated diseases and aging. Conclusion: Genetic-environmental interactions seem to contribute to the dynamic nature of somatic mosaicism. Accordingly, an external influence on cellular populations may shift the ratio of karyotypically normal and abnormal cells in favor of an increase in the amount of cells without chromosome rearrangements. Taking into account the role of somatic chromosomal mosaicism in health and disease, we have hypothesized that artificial changing of somatic mosaicism rates may be beneficial in individuals suffering from the associated diseases and/or behavioral or reproductive problems. In addition, such therapeutic procedures might be useful for anti-aging strategies (i.e. possible rejuvenation through a decrease in levels of chromosomal mosaicism) increasing the lifespan. Finally, the hypothesis appears to be applicable to any type of somatic mosacism.

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“…group on the ribose sugar, which can attack the sugar-phosphate backbone, generating breaks with genotoxic outcomes [5]. The DNA must, therefore, be carefully duplicated for proper transmission of the genetic information over many generations, avoiding mutations that can promote genome instability and related human pathologies, like cancer or neurodegenerative diseases [6,7]. The accuracy of DNA replication is ensured not only by the high-fidelity rate of replicative DNA polymerases and their associated proofreading activities but also by numerous other replicative and post-replicative factors and mechanisms, including DNA repair systems [8,9].…”

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confidence: 99%

One, No One, and One Hundred Thousand: The Many Forms of Ribonucleotides in DNA

Nava

Grasso

Sertic

et al. 2020

IJMS

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In the last decade, it has become evident that RNA is frequently found in DNA. It is now well established that single embedded ribonucleoside monophosphates (rNMPs) are primarily introduced by DNA polymerases and that longer stretches of RNA can anneal to DNA, generating RNA:DNA hybrids. Among them, the most studied are R-loops, peculiar three-stranded nucleic acid structures formed upon the re-hybridization of a transcript to its template DNA. In addition, polyribonucleotide chains are synthesized to allow DNA replication priming, double-strand breaks repair, and may as well result from the direct incorporation of consecutive rNMPs by DNA polymerases. The bright side of RNA into DNA is that it contributes to regulating different physiological functions. The dark side, however, is that persistent RNA compromises genome integrity and genome stability. For these reasons, the characterization of all these structures has been under growing investigation. In this review, we discussed the origin of single and multiple ribonucleotides in the genome and in the DNA of organelles, focusing on situations where the aberrant processing of RNA:DNA hybrids may result in multiple rNMPs embedded in DNA. We concluded by providing an overview of the currently available strategies to study the presence of single and multiple ribonucleotides in DNA in vivo.

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Chromosome Instability in the Neurodegenerating Brain

Cited by 36 publications

References 36 publications

Contributions of DNA Damage to Alzheimer’s Disease

Contributions of DNA Damage to Alzheimer’s Disease

Dynamic nature of somatic chromosomal mosaicism, genetic-environmental interactions and therapeutic opportunities in disease and aging

One, No One, and One Hundred Thousand: The Many Forms of Ribonucleotides in DNA

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