GINnCIN hypothesis of brain aging: deciphering the role of somatic genetic instabilities and neural aneuploidy during ontogeny

摘要

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.