Mechanisms and consequences of aneuploidy and chromosome instability in the aging brain

Abstract

Aneuploidy and polyploidy are a form of Genomic Instability (GIN) known as Chromosomal Instability (CIN) characterized by sporadic abnormalities in chromosome copy numbers. Aneuploidy is commonly linked to pathological states. It is a hallmark of spontaneous abortions and birth defects and it is observed virtually in every human tumor, therefore being generally regarded as detrimental for the development or the maturation of tissues under physiological conditions. Polyploidy however, occurs as part of normal physiological processes during maturation and differentiation of some mammalian cell types. Surprisingly, high levels of aneuploidy are present in the brain, and their frequency increases with age suggesting that the brain is able to maintain its functionality in the presence of high levels of mosaic aneuploidy. Because somatic aneuploidy with age can reach exceptionally high levels, it is likely to have long-term adverse effects in this organ. We describe the mechanisms accountable for an abnormal DNA content with a particular emphasis on the CNS where cell division is limited. Next, we briefly summarize the types of GIN known to date and discuss how they interconnect with CIN. Lastly we highlight how several forms of CIN may contribute to genetic variation, tissue degeneration and disease in the CNS.

“Amyloid‐beta accumulation cycle” as a prevention and/or therapy target for Alzheimer's disease

“…However, compared with healthy subjects, patients with both familial/early‐onset and sporadic late‐onset AD show widespread aneuploidy in their brains and in peripheral blood cells (Bajic, Spremo‐Potparevic, Zivkovic, Isenovic, & Arendt, ; Hou, Song, Croteau, Akbari, & Bohr, ; Iourov et al, ; Lee, Thomas, & Fenech, ; Zivković et al, ). This AD‐associated aneuploidy is thought to be due to genomic instability (Andriani, Vijg, & Montagna, ; Shepherd, Yang, & Halliday, ). This observation suggests the existence of a cell population that has newly entered a flawed cell cycle in patients with AD.…”

Rescue from replication stress during mitosis

“…Moreover, mutations in the gene encoding for Senataxin (SETX), a protein involved in resolving collisions between transcription and replication and, therefore, preventing R-loop formation, lead to various neurodegenerative diseases, such as amyotrophic lateral sclerosis 4 and ataxia-ocular apraxia 2 106,286 . The molecular link between neurologic diseases and replication stress may lie in the fact that many of the genes involved in brain development are long and are therefore more susceptible to collisions between transcription and replication, 127 transcription-associated DNA damage, or replication stress-induced segregation defects and aneuploidy 287 …”

Whole Chromosome Instability induces senescence and promotes SASP

“…Numerical whole chromosome instability ( W-CIN ) is a cellular state with a high propensity for chromosome mis-segregation generated by defects in the mitotic machinery and in cellular pathways controlling chromosome segregation, such as the Spindle Assembly Checkpoint ( SAC ) and sister chromatid cohesion 3 4 . Accordingly, deficient expression of components from either pathway results in W-CIN in vitro and in vivo 5 6 7 8 .…”

“…Several mammalian tissues undergo changes in ploidy during normative aging, such as the brain 9 , liver 10 , lymphocytes 11 , oocytes 12 , lungs, kidney and heart 13 . Interestingly, decreased levels of SAC, cohesin and kinetochore proteins are observed in tissues that undergo age-related aneuploidization 3 14 15 , which could be causative of W-CIN generation at older age.…”