The role of epigenomics in the neurodegeneration of ataxia-telangiectasia.

Abstract

Ataxia-telangiectasia (A-T) is a multisystem disease characterized by neurodegeneration in the CNS [1–5]. The earliest and most profound neuropathology involves the Purkinje and granule cells of the cerebellum. A-T is caused by mutation of the A-T mutated (ATM) gene, which is ubiquitously expressed throughout development and encodes a serine/threonine protein kinase of the phosphatidylinositol-3 kinase-related kinase family [6]. A-T is classified as a rare neurodegenerative disease, mainly impacting on cerebellum integrity and functioning, resulting in a progressive deterioration of motor functional capabilities [5]. Moreover, since there is currently no effective treatment to cure or even slow down the rate of cerebellar neurodegeneration, A-T significantly decreases life quality of those suffering from it. The best-known function of ATM is to ensure the integrity of the genome. After DNA damage, ATM activates cell cycle checkpoints, arresting the cycle until DNA repair is complete [7]. Its role in maintaining the health and survival of neurons is complex. Consistent with its function in DNA damage repair [8], ATM protects postmitotic neurons from degeneration by suppressing the cell cycle [9–11]. While non-neurological phenotypes are also found, including immune system defects, germ cell defects, hypersensitivity to ionizing radiation and increased susceptibility to, it is the origins of the CNS motor phenotypes of A-T that are the most poorly understood. Yet the pathway that leads from these defects to neuronal cell loss and the other classical neurological phenotypes remains unknown. Epigenetic systems, heritable changes in gene expression that do not involve coding sequence modifications, include DNA methylation, histone modifications and chromatin remodeling, and noncoding RNA regulation. These types of changes have been proposed to be responsible for controlling the expression and function of genes and have emerged as important mediators of development and aging [12–19]. Several diseases are known to have a multifactorial origin, depending not only on genetic but also on environmental factors. They are called ‘complex disorders’ and include cardiovascular disease, cancer, diabetes, and neuropsychiatric and neurodegenerative diseases [20–26]. The neurological disorder most intensely studied with regard to epigenetic changes is Rett syndrome; patients with Rett syndrome have neurodevelopmental defects associated with mutations in MeCP2, which encodes the methyl CpG binding protein 2, that binds to methylated DNA. Other mental retardation disorders are also linked to the disruption of genes involved in epigenetic mechanisms; such disorders include α thalassaemia/mental retardation X-linked syndrome, Rubinstein–Taybi syndrome, and Coffin–Lowry syndrome [26]. Due to epigenetic variability among different neuronal cell types and epigenetic instability during development and maturation of neurons, whether specific epigenetic system is involved in the vulnerability of ATM-deficient Purkinje cell with a large and pale nuclei will be helpful to understand A-T neurodegeneration. In this review, we place emphasis both on addressing nuclear accumulation of histone The role of epigenomics in the neurodegeneration of ataxia-telangiectasia