Epigenetic mechanisms during ageing and neurogenesis as novel therapeutic avenues in human brain disorders

Abstract

Ageing is the main risk factor for human neurological disorders. Among the diverse molecular pathways that govern ageing, epigenetics can guide age-associated decline in part by regulating gene expression and also through the modulation of genomic instability and high-order chromatin architecture. Epigenetic mechanisms are involved in the regulation of neural differentiation as well as in functional processes related to memory consolidation, learning or cognition during healthy lifespan. On the other side of the coin, many neurodegenerative diseases are associated with epigenetic dysregulation. The reversible nature of epigenetic factors and, especially, their role as mediators between the genome and the environment make them exciting candidates as therapeutic targets. Rather than providing a broad description of the pathways epigenetically deregulated in human neurological disorders, in this review, we have focused on the potential use of epigenetic enzymes as druggable targets to ameliorate neural decline during normal ageing and especially in neurological disorders. We will firstly discuss recent progress that supports a key role of epigenetic regulation during healthy ageing with an emphasis on the role of epigenetic regulation in adult neurogenesis. Then, we will focus on epigenetic alterations associated with ageing-related human disorders of the central nervous system. We will discuss examples in the context of psychiatric disorders, including schizophrenia and posttraumatic stress disorders, and also dementia or Alzheimer's disease as the most frequent neurodegenerative disease. Finally, methodological limitations and future perspectives are discussed.

Keywords: DNA methylation; Epidrug; Epigenetics; Histone modifications; Neurodegeneration; Neurogenesis; Psychiatric disorders.

Fig. 1

Epigenetic therapy in neuropsychiatric disorders. A combination of external and internal factors can induce epigenetic changes in the normal healthy brain during ageing but also under pathological conditions, including neurodegenerative disorders or psychiatric diseases. Epigenetic therapy, such as pharmacological treatment with DNA-demethylating drugs or HDAC inhibitors, can reverse the distorted epigenetic modifications and induce specific gene expression programs. Two main strategies can be achieved: first, the use of epigenetic drugs can induce adult neurogenesis by enhancing cellular reprogramming from neural precursor cells and, second, changes in epigenetic modifications can reverse gene expression of genes involved in neuronal dysfunction and relevant for the disease