GIN'n'CIN hypothesis of brain aging: deciphering the role of somatic genetic instabilities and neural aneuploidy during ontogeny

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.

Figure 1

The fate of an aneuploid neuron. It seems that there are two most probable ways. Firstly, aneuploid neuron can be integrated into neuronal circuitry. This has the potential to produce disease phenotype (through affecting all the elements of the circuitry via synaptic activity of aneuploid neuron) or this could be a probable mechanism of aging; alternatively, if aneuploidy rates are relatively low, integration of aneuploid neuron into neuronal circuitry is suggested to be a mechanism for neuronal diversity. Secondly, aneuploid neuron can be subjected to neuronal cell death. The latter could be associated with large-scale neuronal cell clearance that has potential to lead to brain diseases or, alternatively, to be an aging mechanism.

Figure 2

The key points of the hypothesis. The developing human brain (12-15 weeks' gestation) exhibit 30-35% of aneuploid cells [28], which are formed during neurogenesis (prenatal brain development). This process becomes exhausted soon after birth. At later developmental stage, adult neurogenesis starts, being, however, significantly less productive in terms of the amount of cells formed. Abnormal clearance of aneuploid cells leads to postnatal brain diseases, which are featured by GIN and CIN confined to the brain. Some of these diseases are associated with accelerated aging (i.e. Alzheimer's disease and ataxia-telangiectasia). Normal brain development leads to decrease of aneuploidy rates, which achieves averagely 10% [9,10,14]. The presence of aneuploid cells in the brain from the early prenatal development to the late ontogeny is hypothesized to give rise to GIN and CIN in the brain of elderly individuals. This is partially confirmed by analyzing controls in molecular neurocytogenetic studies of the diseased brain [5,7,12-14,16-20]. Mitotic errors during adult neurogenesis can also produce aneuploid cells throughout aging.