A study of the polycomb group complexes in the maintenance of heterochromatic genome stability and Alzheimer's disease
Alzheimer’s disease (AD) is the most common neurodegenerative disorder characterized by progressive and irreversible decline in cognitive functions and thinking skills. There are two types of AD: early-onset or familial AD (EOAD) that accounts for 5% of cases and is linked to mutations affecting the amyloid metabolism and late-onset or sporadic AD (LOAD), which accounts for 95% of cases, however the etiology of this type remains poorly delineated with ageing presenting the main risk factor. Epigenetic changes involving histone modifications play a critical role in ageing and age- related neurodegenerative diseases. Recent evidence describing LOAD as an epigenetic disorder has accrued, associating this disorder to global genomic instability.  Polycomb group proteins are epigenetic modifiers initiating chromatin remodeling and gene repression at facultative heterochromatin. We report that mice heterozygous for a polycomb protein develop with advancing age a neurological disorder resembling LOAD characterized by impaired memory behaviour, tau phosphorylation, amyloid accumulation, and synaptic dysfunction. Interestingly, this phenotype was preceded by neuronal heterochromatin decondensation and activation of DNA damage response. Concomitantly, polycomb deficiency, de-compaction of neuronal heterochromatin, and accumulation of DNA damage machinery were also characteristic of LOAD brains. Remarkably, DNA damage was not randomly distributed on the genome but enriched at heterochromatin. The findings presented in this thesis identified specific epigenetic modifications that lead to aberrant genomic instability in LOAD and will aid in the development of novel therapeutics, which may potentially slow neurodegeneration.
Polycomb Late-Onset Alzheimer's disease genomic instability heterochromatin