Epigenetic mechanisms during ageing and neurogenesis as novel therapeutic avenues in human brain disorders.
Epigenetic mechanisms during ageing and neurogenesis as novel therapeutic avenues in human brain disorders.
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DOI：
10.1186/s13148-017-0365-z
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发表时间：
2017
影响因子：
5.7
通讯作者：
Berdasco M
中科院分区：
文献类型：
--
作者：
Delgado-Morales R;Agís-Balboa RC;Esteller M;Berdasco M
衰老是人类神经系统疾病的主要危险因素。在控制衰老的多种分子途径中，表观遗传学可以部分通过调节基因表达以及通过调节基因组不稳定性和高阶染色质结构来引导与年龄相关的衰退。表观遗传机制参与神经分化的调节以及健康寿命期间与记忆巩固、学习或认知相关的功能过程。另一方面，许多神经退行性疾病与表观遗传失调有关。表观遗传因子的可逆性质，特别是它们作为基因组和环境之间中介的作用，使它们成为令人兴奋的治疗靶点。在这篇综述中，我们并没有对人类神经系统疾病中表观遗传失调的途径进行广泛的描述，而是重点关注表观遗传酶作为药物靶标的潜在用途，以改善正常衰老过程中，特别是神经系统疾病中的神经衰退。我们将首先讨论支持表观遗传调控在健康衰老过程中关键作用的最新进展，重点是表观遗传调控在成人神经发生中的作用。然后，我们将重点关注与衰老相关的人类中枢神经系统疾病相关的表观遗传改变。我们将讨论精神疾病的例子，包括精神分裂症和创伤后应激障碍，以及痴呆症或阿尔茨海默病作为最常见的神经退行性疾病。最后，讨论了方法的局限性和未来的前景。
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.