Chromosome Instability in the Neurodegenerating Brain
Chromosome instability (CIN) is a hallmark of cancer (Heng, 2015; Rangel et al., 2017; Machiela, 2019; Simonetti et al., 2019). Additionally, a number of neurodegenerative diseases (NDD) demonstrate CIN, which mediates neuronal cell loss and appears to be a key element of the pathogenic cascade (Iourov et al., 2009a; Iourov et al., 2009b; Arendt et al., 2010; Jeppesen et al., 2011; Driver, 2012; Bajic et al., 2015; Leija-Salazar et al., 2018; Nudelman et al., 2019). Moreover, CIN is repeatedly associated with aging and aging-related deterioration of the brain (Yurov et al., 2010; Kennedy et al., 2012; Andriani et al., 2017; Vijg et al., 2017; Zhang and Vijg, 2018). Despite numerous studies dedicated to CIN in NDD, there is still no clear understanding of differences between “cancerous” and “neurodegenerative” CINs. Here, we propose a theoretical model, which seems to highlight the differences between these CIN types. Oncogenic parallels have long been observed in NDD. More specifically, CIN manifesting as aneuploidy (gains or losses of whole chromosomes) has been systematically identified in the brain of individuals with NDD. The Alzheimer’s disease brain has been found to demonstrate high rates of spontaneous aneuploidy (Iourov et al., 2009b; Iourov et al., 2011; Yurov et al., 2014; Bajic et al., 2015; Arendt et al., 2017; Yurov et al., 2018). Furthermore, Alzheimer’s disease genes are involved in molecular pathways, alterations to which result in chromosome mis-segregation and aneuploidy (Granic et al., 2010). Similarly, CIN syndromes and/or mutations in genes involved in cell cycle/ mitotic checkpoint pathways exhibit brain-specific CIN associated with neurodegeneration. Thus, CIN has been demonstrated to underlie neurodegenerative processes (Iourov et al., 2009a; Caneus et al., 2018; Leija-Salazar et al., 2018). Additionally, submicroscopic CIN producing structural rearrangements of the APP gene (21q21.3) has been shown to be involved in neurodegenerative pathways to Alzheimer’s disease (Bushman et al., 2015; Lee et al., 2018). It is important to note that numerical CIN (aneuploidy) is shown to be implicated in the neurodegeneration pathway inasmuch as the neurons affected by CIN/aneuploidy are susceptible to selective cell death (Arendt et al., 2010; Fricker et al., 2018; Iourov et al., 2019). Finally, DNA repair deficiency (Jeppesen et al., 2011) and DNA replication stress (Yurov et al., 2011) have been identified as possible mechanisms for neurodegeneration. Another body of evidence for the contribution of CIN to neurodegeneration is provided by brain aging studies. Actually, CIN and related phenomena (aneuploidization, somatic mutagenesis, etc.) are considered to be elements of a global pathogenic cascade resulting in aging phenotypes (Kennedy et al., 2012; Vijg, 2014; Andriani et al., 2017). Progressive accumulation of somatic chromosomal mutations (aneuploidy) causing numerical CIN is suggested to be implicated in cellular senescence and tissue aging (Yurov et al., 2010; Zhang and Vijg, 2018; Iourov et al., 2019). For instance, rates of X chromosome aneuploidy increase with age in the Alzheimer’s disease brain (Yurov et al., 2014). It is to note that X chromosome aneuploidy (loss/monosomy) is a cytogenetic biomarker of human aging (Vijg, 2014; Zhang and Vijg, 2018; Iourov et al., 2019). Genome instability at the Edited by: Anja Weise, University Hospital Jena, Germany