Abstract
Genomic instability (GIN) and chromosome instability (CIN) are two closely related ways to produce a variety of pathogenic conditions, i.e. cancer, neurodegeneration, chromosomal and genomic diseases. The GIN and CIN manifestation that possesses the most appreciable impact on cell physiology and viability is aneuploidy. The latter has been consistently shown to be associated with aging. Classically, it has been considered that a failure of mitotic machinery leads to aneuploidy acquiring throughout aging in dividing cells. Paradoxically, this model is inapplicable for the human brain, which is composed of post-mitotic cells persisting throughout the lifetime. To solve this paradox, we have focused on mosaic neural aneuploidy, a remarkable biomarker of GIN and CIN in the normal and diseased brain (i.e. Alzheimer's disease and ataxia-telangiectasia). Looking through the available data on genomic variations in the developing and adult human central nervous system, we were able to propose a hypothesis suggesting that neural aneuploidy produced during early brain development plays a crucial role of genetic determinant of aging in the healthy and diseased brain.
Highlights
Aneuploidy has been consistently shown to be associated with aging [1,2,3,4,5]
We have focused on mosaic neural aneuploidy, a remarkable biomarker of Genomic instability (GIN) and chromosome instability (CIN) in the normal and diseased brain (i.e. Alzheimer's disease and ataxia-telangiectasia)
We propose that mitotic errors during adult neurogenesis produce small amount of aneuploid brain cells, and this peculiarly contributes to GIN/CIN manifested as increased aneuploidy in late ontogeny
Summary
Aneuploidy has been consistently shown to be associated with aging [1,2,3,4,5]. there is no consensus on how aneulpoidization and aging are interconnected. The dilemma might be solved by addressing adult neurogenesis research that has depicted the possibility of the adult mammalian brain to generate new neuronal cells [15] These data is unable to provide complete explanation of aging-related changes within the content of chromosomal DNA in the normal and diseased human brain, which indicates aneuploidy association with brain aging phenotypes [7,9,10,11,12,13,14,16,17,18,19,20]. To make a clear presentation of our hypothesis, we found pertinent first to provide a description of brainspecific GIN/CIN occurrence at different ontogeny stages and in brain diseases, especially when accompanied by accelerated aging It has been long debated whether the mammalian brain is populated by cells with abnormal chromosome numbers (polyploid cells) [7,29,30,31].
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