Epigenetic programming of neurodegenerative diseases by an adverse environment

Abstract

Experience and environment can critically influence the risk and progression of neurodegenerative disorders. Epigenetic mechanisms, such as miRNA expression, DNA methylation, and histone modifications, readily respond to experience and environmental factors. Here we propose that epigenetic regulation of gene expression and environmental modulation thereof may play a key role in the onset and course of common neurological conditions, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. For example, epigenetic mechanisms may mediate long-term responses to adverse experience, such as stress, to affect disease susceptibility and the course of neurodegenerative events. This review introduces the epigenetic components and their possible role in mediating neuropathological processes in response to stress. We argue that epigenetic modifications will affect neurodegenerative events through altered gene function. The study of epigenetic states in neurodegenerative diseases presents an opportunity to gain new insights into risk factors and pathogenic mechanisms. Moreover, research into epigenetic regulation of disease may revolutionize health care by opening new avenues of personalized, preventive and curative medicine.

Introduction

The notion that the environment influences the phenotype of a living organism goes back to Jean–Baptiste Lamarck's concept of the driving forces of evolution (Lamarck, 1914). Rapid progress in genetic and epigenetic analysis technologies over the recent years has revolutionized the depth of understanding of the environmental impact on brain function and adaptation far beyond the early notions of Lamarck. In addition, the completion of the Human Genome Project and the commencement of the Human Epigenome Project opened new avenues for life sciences and biomedical research (http://www.epigenome.org).

The nature of genetic and epigenetic changes in response to environmental stimuli has received particular attention in the quest to understand the origins of disease. Whereas genetics involves permanent and mostly irreversible changes to DNA sequence, epigenetics is thought to concern mainly transient and reversible changes to chromatin and gene expression (Wu and Morris, 2001). Although tremendous breakthroughs have been made in the search for genetic and epigenetic patterns linked to disease, a comprehensive explanation of the mechanisms that underlie phenotypic plasticity is still far from being realistic. However, epigenetic regulation of gene expression has been identified as a key player in producing rapid adaptation to changing environmental conditions both within a single lifespan as well as across multiple generations. These mechanisms particularly apply to the brain, which is capable of changing readily in response to experience throughout a lifetime.

The discovery that the brain changes in response to experience began with early studies by Ramon y Cajal (Cajal, 1928). It is assumed that experience and environment are major factors to determine neuronal plasticity and susceptibility to neurological diseases (Crews, 2008). Although the concept of brain plasticity has now become central to neuroscientific studies, the enormous power of epigenetic regulation to determine brain plasticity and its output behavior has become recognized mainly in the past ten years. Ultimately, the epigenome may represent a critical link to understanding not only adaptive responses of the brain to beneficial experience, but also to elucidate mechanisms of pathological processes induced by adverse experience, such as stress.

Stress likely represents a critical influence on neuronal function and disease. The term stress refers to perturbation of homeostasis by a stressful event causing the onset of complex neural and endocrine adaptations characterized by activation of the hypothalamic–pituitary–adrenal (HPA) axis, which prompts the release of glucocorticoid hormones from the adrenal gland. Glucocorticoids act throughout the body, but very prominently their actions are focused on the brain. Excessive or chronically elevated glucocorticoid levels in particular can compromise neuronal survival and diminish the plastic capacity of the brain (Sapolsky, 2000a, Sapolsky, 2000b, Sapolsky, 2000c). The effects of physiological stress on neuronal integrity and survival involve cellular and biochemical processes including compromised chemoresistance to oxidative stress (Landriscina et al., 2009), exaggerated activation of inflammatory cascades (Matsunaga et al., 2011, Sorrells et al., 2009), altered neurotrophic factor expression (Smith et al., 1995) or facilitated cytoplasmic protein accumulation (Sotiropoulos et al., 2011). Epigenetic programming through previous experience may determine the ability of the brain to adapt to a stressful environment in the long term. Maladaptive epigenetic programming by chronic stress, however, may enhance the vulnerability to stress and place the brain at a higher risk of neurodegenerative events.

The aim of this review is to provide an overview of possible epigenetic mechanisms involved in the pathology of neurodegenerative disease. A specific focus will be on the role of stressful experiences in altering epigenetic regulation of gene expression. We propose that chronic stress may affect the course of neurodegenerative events through DNA methylation, chromatin remodeling and histone modification, and microRNA (miRNA) expression. We hypothesize that epigenetic regulation in response to chronic stress may contribute to the pathogenesis of common neurodegenerative diseases.