Chromosome Instability and Mosaic Aneuploidy in Neurodegenerative and Neurodevelopmental Disorders

Abstract

Evidence from multiple laboratories has accumulated to show that mosaic neuronal aneuploidy and consequent apoptosis characterizes and may underlie neuronal loss in many neurodegenerative diseases, particularly Alzheimer’s disease and frontotemporal dementia. Furthermore, several neurodevelopmental disorders, including Seckel syndrome, ataxia telangiectasia, Nijmegen breakage syndrome, Niemann–Pick type C, and Down syndrome, have been shown to also exhibit mosaic aneuploidy in neurons in the brain and in other cells throughout the body. Together, these results indicate that both neurodegenerative and neurodevelopmental disorders with apparently different pathogenic causes share a cell cycle defect that leads to mosaic aneuploidy in many cell types. When such mosaic aneuploidy arises in neurons in the brain, it promotes apoptosis and may at least partly underlie the cognitive deficits that characterize the neurological symptoms of these disorders. These findings have implications for both diagnosis and treatment/prevention.

The Cytogenomic “Theory of Everything”: Chromohelkosis May Underlie Chromosomal Instability and Mosaicism in Disease and Aging

“…This cascade of CIN/GIN processes results in somatic mosaicism and CIN, which are mechanisms for cancer, infertility, brain diseases, aging, and, probably, other morbid conditions. To depict biological basis of chromohelkosis, we have used parts of figures from our previous articles distributed under the terms of the Creative Commons Attribution License [28,48].…”

“…SMC and CIN are important contributors to development, homeostasis, interindividual diversity and disease. To be more exact, SMC and CIN are integrated parts of human prenatal development [38][39][40], aging [41,42], cancer [24,43,44], interindiviudal/intercellular genome diversification and disease [45][46][47][48][49][50][51]. SMC and CIN are considered an major focus of basic and diagnostic research for providing therapeutic opportunities in disease and aging [29,[51][52][53].…”

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

“…It is not surprising inasmuch as chromosomal mosaicism and instabilities are risk factors for cancers [73,74]. In general, aging-related diseases are commonly mediated by chromosomal instability and/or mosaic aneuploidy [7,41,44,45,55,[75][76][77]. The results of molecular genetic studies of aging correlate with observations on mutation load contribution to limiting/ shortening the lifespan [78,79].…”

“…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].…”

Aneuploidy and DNA Methylation as Mirrored Features of Early Human Embryo Development

“…After birth, the level of DNA methylation remains constant and then changes, including global hypomethylation and region-specific hypermethylation, with aging and age-related disease development [100]. At the same time, there is an increase in the aneuploidy frequency in cells during both normal aging [101] and various pathologies, including malignant tumors [102] and neurodegenerative diseases [103].…”