Involvement of Histone PTMs in DNA Repair Processes in Relation to Age-Associated Neurodegenerative Disease

Abstract

Neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD), are becoming common in the world with increasing number of aged people in the population. Many investigations have been performed in an attempt to elucidate the mechanisms of neurodegenerative diseases. However, no single etiopathological factor was found to be responsible for such diseases, and therefore no effective therapeutic strategy could be designed. Aging is regarded as the greatest risk factor for the development of neurodegenerative diseases. Upon aging, reactive oxygen species (ROS) accumulation induces damage to DNA as well as protein and lipid, thus resulting in a progressive loss in the functional efficiency of the brain. Recently, it has been demonstrated that hundreds of proteins including KIN-19, a homolog of mammalian casein kinase 1 isoform alpha (CK1a), become more insoluble with age in Caenorhabditis elegans and its over-expression could enhance polyglutaminerepeat pathology (David et al., 2010). Such discovery indicated that aging process itself could be a causative factor for protein aggregation. Increasing aggregation of proteins, such as amyloid beta peptide, could also promote the generation of ROS, DNA damage and thus accelerate neurodegenerative events (Butterfield, 2002). In addition, redox-active metals Cu and Fe could also generate ROS. Normal aging resulted in an elevation of Cu and Fe in the brain, and further interruption of metal homeostasis was noted in AD (Tabner et al., 2010). Oxidative DNA lesions, such as 8-oxoguanine (8-oxoG) and 8-hydroxyguanosine (8-OHG), were increased dramatically in patients with PD (Nakabeppu et al., 2007; Lovell et al., 1999). Statistically significant elevation of 8-hydroxy-2'-deoxyguanosine (8-OHdG) was detected on DNA of AD subjects, even at the early stage of AD (Lovell et al., 1999; Markesbery & Lovell, 2006). At the same time, DNA repair deficiency in aged or neurodegenerative brain was observed. Both base excision repair (BER) and non-homologous end joining (NHEJ) pathway were deficient in AD subjects (Shackelford, 2006; Weissman et al., 2007). The animals with deficiencies in DNA repair exhibited neurological abnormalities or severe postnatal neurodegeneration and shortened life span (Laposa & Cleaver, 2001; Best, 2009; Dolle et al., 2006), that proved the role of DNA repair deficiency in neurodegeneration. DNA damage combined with inefficient repair mechanism could induce the apoptosis of