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.

Keywords: aging; aneuploidy; brain diseases; chromosome; chromosome instability; genome instability; neurodegeneration.

Figure 1

Schematic depiction of changes in chromosome instability CIN rates in the context of brain aging and neurodegeneration indicating trends of brain-specific CIN rates through ontogeny and/or the course of life and suggested periods of progressive neuronal cell death in health and disease (natural and neurodegeneration, respectively): 1 or reddish trendline—CIN trend for early onset neurodegenerative diseases with accelerated aging phenotypes, e.g., ataxia-telangiectasia; 2 or blueish trendline—CIN trend for late onset neurodegenerative diseases; 3 or yellowish trendline—natural CIN trend.