Chromosome Instability, Aging and Brain Diseases

Abstract

Chromosome instability (CIN) has been repeatedly associated with aging and progeroid phenotypes. Moreover, brain-specific CIN seems to be an important element of pathogenic cascades leading to neurodegeneration in late adulthood. Alternatively, CIN and aneuploidy (chromosomal loss/gain) syndromes exhibit accelerated aging phenotypes. Molecularly, cellular senescence, which seems to be mediated by CIN and aneuploidy, is likely to contribute to brain aging in health and disease. However, there is no consensus about the occurrence of CIN in the aging brain. As a result, the role of CIN/somatic aneuploidy in normal and pathological brain aging is a matter of debate. Still, taking into account the effects of CIN on cellular homeostasis, the possibility of involvement in brain aging is highly likely. More importantly, the CIN contribution to neuronal cell death may be responsible for neurodegeneration and the aging-related deterioration of the brain. The loss of CIN-affected neurons probably underlies the contradiction between reports addressing ontogenetic changes of karyotypes within the aged brain. In future studies, the combination of single-cell visualization and whole-genome techniques with systems biology methods would certainly define the intrinsic role of CIN in the aging of the normal and diseased brain.

Klinefelter syndrome mosaicism in boys with neurodevelopmental disorders: a cohort study and an extension of the hypothesis

“…Moreover, dynamic nature of somatic chromosomal mosaicism leads to the involvement in pathogenetic and ontogenetic processes [ 7 , 36 , 37 ]. These processes are further involved in intercellular genetic (genomic) diversity [ 35 , 38 , 39 ], early-onset brain diseases [ 7 , 10 , 28 , 40 , 41 ], late-onset brain diseases [ 34 , 42 – 46 ], behavior [ 47 ], and aging [ 43 , 48 – 51 ]. Therefore, the analysis of KSM in the context of brain diseases seems to be required.…”

“…Supernumerary chromosome X seems to be a critical element of the pathogenetic cascade of psychiatric diseases observed with high frequency in Klinefelter syndrome [ 5 , 11 , 13 – 16 ]. Moreover, since aneuploidy levels are age-dependent and are involved in normal and pathogenic aging [ 7 , 37 , 48 – 51 ], it is highly likely that KSM levels are able to change with age. The dynamic nature of KSM exhibited by cases associated with multiple aneuploidy and structurally rearranged chromosomes X supports this assumption.…”

Cytosolic Self-DNA—A Potential Source of Chronic Inflammation in Aging

“…Thus, all living organisms have evolved mechanisms to repair DNA lesions and to maintain genome stability and integrity [ 54 ]. Evidence indicates that DNA damage and mutation accumulate with age in multiple tissues across species [ 55 , 56 , 57 , 58 , 59 ]. DNA damage and genome instability can contribute to aging in various ways, for instance, by perturbing normal gene expression, persistent and elevated DNA damage response signaling, apoptosis, and cellular senescence [ 56 ].…”

COVID-19 and Aging-Related Genome (Chromosome) Instability in the Brain: Another Possible Time-Bomb of SARS-CoV-2 Infection

“…However, the intrinsic effects of COVID-19 on the human brain remain a matter of future research (Pennisi et al, 2020 ). Pathological brain aging and natural brain deterioration are associated with accumulation and propagation of genome (chromosome) instability (Yurov et al, 2010 , 2019 ; Andriani et al, 2017 ; Zhang and Vijg, 2018 ; Iourov et al, 2021 ). Since genome (chromosome) instability may result from viral infections (Heng, 2019 ), SARS-CoV-2 interactions with cells of the central nervous system are able to increase the risk for early manifestations of aging-related brain disorders and/or premature brain deterioration mediated by genome and chromosome instability.…”

“…Brain-specific genomic variations [including aneuploidy (loss/gain of whole chromosomes) and single gene mutations] are associated with a wide spectrum of late-onset brain diseases (Yurov et al, 2010 ; Rohrback et al, 2018 ; Iourov et al, 2021 ). More importantly, chromosome instability mediates neurodegeneration (Iourov et al, 2009 ; Rohrback et al, 2018 ; Yurov et al, 2019 ).…”