ReviewCohesion and the aneuploid phenotype in Alzheimer's disease: A tale of genome instability
Introduction
The aneuploid phenotype in Alzheimer's disease (AD) (Mosch et al., 2007) lead to the conclusion that the AD cell has impaired regulation of cohesion and may have an activated cell cycle checkpoint pathway that renders it “ahead of its time”. Still, mechanisms that regulate the AD cell do not favor abrogation of the G2/M phase. Despite that various mitotic markers are up regulated in vulnerable neurons in AD and DNA in these neurons is successfully replicated (i.e., proceeds to S phase), no evidence of an actual mitosis has ever been found (Herrup, 2012). This suggests that neuronal cells are arrested at a point(s) prior to the actual event of cellular division and therefore must either complete the cycle or die. Alteration of centromere-cohesion dynamics may play an intrinsic role in cell death by mitotic catastrophe and/or apoptosis by inducing genomic instability or premature centromere division (PCD) leading to aneuploidy (Bajic et al., 2008, Cimini and Degrassi, 2005).
Section snippets
Cohesion and cohesin
The centromere and chromatid arms are held by a protein called cohesin (Nasmyth, 2005, Nasmyth and Haering, 2009). Cohesin contains two structural maintenance of cohesion subunits (SMC), SMC1 and SMC3, and two non-SMC subunits, Scc1 (Rad21) and Scc3. The activity of cohesion is also dependent on interactions with regulatory factors, including PDS5, Scc2, Scc4 and ECO 1 (Barbero, 2011, Nasmyth and Haering, 2009). Cohesin is loaded onto chromosomes before S phase and establishes cohesion between
Relevance of aneuploidy in genome instability and variability in AD
Cells of an adult human body are susceptible to DNA changes, and approximately 104 to 105 of DNA lesions per cell/per day may occur (Iourov et al., 2010). Most of the lesions are corrected by repair mechanisms. However, these processes represent one of the exogenous sources of change in the human genome and may be a cause of different pathologic processes (Bucholtz and Demuth, 2013). During the numerous cell divisions in an organism, aneuploidy (i.e., changes in the chromosome number), occurs
Cohesin associated proteins and chromosome stability
The pituitary tumor transforming gene (PTTG) was cloned initially from a rat pituitary tumor. Structural homology suggested that PTTG may be a mammalian securin (an essential protein in cohesion regulation of centromeres) and this has been confirmed by its involvement in regulating sister chromatid separation during mitosis (Jallepali et al., 2001, Mora-Santos et al., 2013).
Overexpression of PTTG activates the expression of p53 and modulates its function, with this action of PTTG being mediated
Anaphase-promoting complex (APC), cohesion dynamics and neurons
The anaphase-promoting complex (APC) is tethered to cohesion in processes of chromosome segregation and separation in mitotic cells and new data show functional activity of APC in post-mitotic neurons in which alterations of this protein may lead to aneuploidy (Cimini and Degrassi, 2005). APC or cyclosome is an E3 ubiquitin protein ligase that together with Cdc20 and Cdh1 targets mitotic proteins for degradation by the proteosome and functions by regulating cell cycle transitions in
CDK 11 a new cell cycle cyclin in cohesion dynamics and APP
Altered cell cycle events in vulnerable neurons precede the occurrence of amyloid-β (Aβ) and neurofibrillary tangles in AD (Herrup, 2010, Smith, 1998, Vincent et al., 1997, Vincent et al., 1996) leading to the degeneration of distinctive neuronal populations in the hippocampus and other cortical brain regions. Ectopic expression of a number of mitosis-specific proteins, cyclins and cycline dependent kinases, have been reported in susceptible neurons in AD (Arendt et al., 1996, Lee et al., 2009,
Conclusion
There has been extensive research in the nature of Aβ and Tau as pathological hallmarks of AD. A number of authors, have reported that alterations of the processes leading to toxic forms of Aβ are also responsible for malsegregation effects in dividing cells (Granic et al., 2010). This led to the hypothesis of the aneuploidogenic phenotype that may be the cause or influence the processes leading to AD, but also other neurodegenerative diseases (Potter et al., 2008; Boeras et al., 2008, Granic
Conflict of interest
The authors declare no financial or non-financial competing interests.
Acknowledgment
Authors thank the Ministry of Education, Science and Technological Development of the Republic of Serbia for financial support (project No. 173034).
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