NRSF and Its Epigenetic Effectors: New Treatments for Neurological Disease
NRSF and Its Epigenetic Effectors: New Treatments for Neurological Disease
复制标题
DOI：
10.3390/brainsci8120226
复制
发表时间：
2018-12
期刊：
影响因子：
3.3
通讯作者：
Ryan Thompson;C. Chan
中科院分区：
文献类型：
--
作者：
Ryan Thompson;C. Chan
神经元限制性沉默因子（NRSF）是众所周知的神经元表型的主转录抑制因子。迄今为止的研究表明，它是神经系统生长和发育的重要参与者。它在神经前体细胞成熟为成年神经元中的作用已经在干细胞模型中得到了很好的表征。虽然从发育的角度已经有很多特征，但研究表明NRSF在各种神经系统疾病中发挥着作用，从神经退行性疾病、神经精神疾病到癌症。NRSF活性的失调破坏了下游基因的表达，这些基因在导致病理状态的几种模型中负责神经元细胞的稳态。有趣的是，现在越来越明显的是，NRSF的失调有助于通过表观遗传机制的神经疾病。虽然NRSF本身是一种转录因子，但其主要效应物是染色质修饰剂。在表观遗传学的水平上，NRSF活性的变化已经在神经性疼痛和癫痫模型中得到了很好的表征。对脑疾病的表观遗传基础的更好理解已经导致设计和使用小分子，其可以通过中和其与染色质重塑物的相互作用来防止NRSF抑制基因表达。本文就NRSF及其辅助因子的基本功能、作用机制及其功能障碍与疾病的关系作一综述。这篇综述还将讨论NRSF作为治疗靶点的研究，并深入研究新的治疗策略，重点是破坏NRSF招募染色质重塑的能力。
The Neuron Restrictive Silencer Factor (NRSF) is the well-known master transcriptional repressor of the neuronal phenotype. Research to date has shown that it is an important player in the growth and development of the nervous system. Its role in the maturation of neural precursor cells to adult neurons has been well characterized in stem cell models. While much has been characterized from a developmental perspective, research is revealing that NRSF plays a role in various neurological diseases, ranging from neurodegenerative, neuropsychiatric, to cancer. Dysregulation of NRSF activity disrupts downstream gene expression that is responsible for neuronal cell homeostasis in several models that contribute to pathologic states. Interestingly, it is now becoming apparent that the dysregulation of NRSF contributes to neurological disease through epigenetic mechanisms. Although NRSF itself is a transcription factor, its major effectors are chromatin modifiers. At the level of epigenetics, changes in NRSF activity have been well characterized in models of neuropathic pain and epilepsy. Better understanding of the epigenetic basis of brain diseases has led to design and use of small molecules that can prevent NRSF from repressing gene expression by neutralizing its interactions with its chromatin remodelers. This review will address the basic function of NRSF and its cofactors, investigate their mechanisms, then explore how their dysfunction can cause disease states. This review will also address research on NRSF as a therapeutic target and delve into new therapeutic strategies that focus on disrupting NRSF’s ability to recruit chromatin remodelers.