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.

Keywords: Aneuploidy; Brain; DNA damage; Genomic instability; Polyploidy; Tissue degeneration; Whole chromosome instability (W-CIN).

Fig. 1

Routes to aneuploidy and tetraploidy. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.) In a CIN state (1, top left) deficiency in SAC signaling (1.1) and merotelic attachments (1.2) result in lagging chromosomes that can generate mononucleated aneuploid cells, aneuploid cells containing a micronucleus, ortetraploid cells (cells in red) due to chromatin bridging and cytokinesis failure (grey area). Tetraploid cells arising from different mechanisms present centrosome amplification (1.3), which in turn can lead to multipolar mitotic spindles and lagging chromosomes. Finally, replication stress (1.4) is a trait of CIN cells that can lead to chromatin bridging and thus, cytokinesis failure or structural rearrangements. Mitotic slippage (2) occurs when the SAC is activated for an extended period of time due to unattached kinetochores and slow Cyclin B degradation. This can result in mitotic exit without cytokinesis and thus tetraploidy. Cell fusion (3) of diploid cells can form atetraploid/polyploid cell. Endoreduplication (4) occurs when DNAis duplicated but mitosis fails to occur, generating a tetraploid and/or polyploid cell. Dysfunctional telomeres (5) can undergo BFB cycles that can lead to chromatin bridging, structural rearrangements and/or cytokinesis failure. Chromosomes with eroded telomeres undergo frequent mis-segregation, and are also a source of aneuploidy. Because micronuclei have been linked to s-CIN and chromothripsis, all defects leading to their formation are hazardous and enable further GIN.

Fig. 2

Down-regulation of components of the SAC and centromere proteins is observed during aging. A trend for reduced expression levels of ploidy-related genes occurs in old mice (16or24-months-old) relative to young (1 month-old) in tissues known to accumulate ploidy changes with age. Female mice (A) lung, (C) heart, (E) brain and (G) kidney. Male mice(B) lung, (D) heart, (F) brain and (H) kidney. Asterisks represent statistically significant differences (p<0.05). Data was plotted from (Zahn et al., 2007).

Fig. 3

ROS are associated with the generation of CIN. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.) ROS can interfere with multiple aspects of the mitotic pathway leading to changes in ploidy (green box). ROS can also induce oxidative post-translational modifications (OPTMs) of proteins important for mitosis and/or cytokinesis, which can result in protein unfolding and malfunction. Thus, oxidative damage to mitotic components could affect their proper activity, leading to abnormal mitosis and CIN. Proteins of the cytoskeleton, molecular motors, kinetochore and centrosomal proteins are found oxidized in a context of oxidative stress (yellow box). It remains to be determined if components of the SAC signaling or the chromosome passenger complex (CPC) are also prone to OPTMs.

Fig. 4

Aneuploidy assessed by four-color interphase FISH in E13.5 embryonic cerebral cortex of WT animals. Interphase FISH is a quantitative and sensitive approach for the analysis of ploidy at the single-cell level, irrespective of the proliferating status of the tested tissue. Examples of diploid and aneuploid cells are highlighted by the dotted line. Ploidy is shown as assigned by the colors of the fluorophores used to label FISH probes.

Fig. 5

General model of functional consequences of CIN. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.) When TP53 is present and functional (top portion of scheme), CIN and CIN-associated DNA damage triggers different types of responses depending on the cell type and on the severity of abnormalities. (1) Aneuploidy provides genetic diversity during neuronal maturation and also selective advantage against stresses in hepatocytes. (2) High CIN has been associated with increased apoptotic frequency and PCD during neural development likely to eliminate cells with abnormal DNA content. (3) Aneuploidy slows proliferation rate and it is detrimental to cell and organismal fitness. (4) CIN generation in vitro and in vivo has also been linked to the induction of senescence. Senescent cells have the ability to change their microenvironment through the secretion of SASP, which comprises several signaling molecules, pro-inflammatory and growth factors. The inflammation generated upon SASP expression has been implicated in the pathology of age-related diseases, early onset of premature aging phenotypes and also in NDs such as AD and PD. Cellular senescence is also thought to contribute directly to NDs because it causes neural stem cell depletion in the adult (blue arrow). In circumstances where TP53 is not functional (bottom portion of scheme), CIN can be a driver of tumorigenesis due to gene dosage imbalances or due to the higher propensity to generate GIN in these cells. In both cases the outcome is growth advantages relative to diploid counterparts. Cells prone to transformation can acquire malignant phenotypes upon interaction with the SASP (i.e., epithelial to mesenchymal transition, increased invasiveness and motility). Induction of senescence in the brain by elevated CIN provides a possible unifying mechanism to explain age-related increase in inflammation and neurodegeneration, as well as the higher incidence of brain tumors that is associated with age (5).