Abstract
Evidence from multiple laboratories has accumulated to show that mosaic neuronal aneuploidy and consequent apoptosis characterizes and may underlie neuronal loss in many neurodegenerative diseases, particularly Alzheimer’s disease and frontotemporal dementia. Furthermore, several neurodevelopmental disorders, including Seckel syndrome, ataxia telangiectasia, Nijmegen breakage syndrome, Niemann–Pick type C, and Down syndrome, have been shown to also exhibit mosaic aneuploidy in neurons in the brain and in other cells throughout the body. Together, these results indicate that both neurodegenerative and neurodevelopmental disorders with apparently different pathogenic causes share a cell cycle defect that leads to mosaic aneuploidy in many cell types. When such mosaic aneuploidy arises in neurons in the brain, it promotes apoptosis and may at least partly underlie the cognitive deficits that characterize the neurological symptoms of these disorders. These findings have implications for both diagnosis and treatment/prevention.
Highlights
Age-associated neurodegenerative diseases exhibit different brain pathologies and different clinical features, and all are associated with reduced neuronal numbers in specific brain regions
The mutations that cause autosomal dominant familial Alzheimer’s disease (FAD) arise in only three genes: the amyloid precursor protein (APP) gene, the presenilin 1 (PSEN1) gene, and the presenilin 2 (PSEN2) gene, all three of which encode proteins involved in the production of the Aβ peptide, which is the main pathogenic molecule of AD (Goate and Hardy, 2012; Hardy, 2017)
Patients with frontotemporal dementia exhibit clinical and pathological characteristics that differ from AD, and most of the autosomal dominantly inherited familial forms of FTLD are caused by a mutation in the MAPT/Tau gene, by a mutation in the progranulin (PRGN) gene, or by a triplet repeat expansion in the C9ORF72 gene, all three of which carry out vastly different normal functions in the cell and are unrelated to the genes mutated in FAD (Rademakers et al, 2012)
Summary
Age-associated neurodegenerative diseases exhibit different brain pathologies and different clinical features, and all are associated with reduced neuronal numbers in specific brain regions. Several neurodevelopmental disorders, including Seckel syndrome, ataxia telangiectasia, Nijmegen breakage syndrome, Niemann–Pick type C, and Down syndrome, have been shown to exhibit mosaic aneuploidy in neurons in the brain and in other cells throughout the body.
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