Targeting specific HATs for neurodegenerative disease treatment: translating basic biology to therapeutic possibilities.
Targeting specific HATs for neurodegenerative disease treatment: translating basic biology to therapeutic possibilities.
复制标题
DOI：
10.3389/fncel.2013.00030
复制
发表时间：
2013
影响因子：
5.3
通讯作者：
Elefant F
中科院分区：
文献类型：
--
作者：
Pirooznia SK;Elefant F
神经元的动态表观遗传调控正在成为神经元适应特定发育和环境线索的转录反应的基本机制。虽然神经表观基因组内的缺陷传统上是在早期发育和遗传性认知障碍的背景下进行研究的，但最近的研究指出，异常组蛋白乙酰化状态是衰老过程中有丝分裂后神经元中基因组结构和功能获得性不适当改变的关键机制。事实上，越来越明显的是，染色质乙酰化状态可以通过与组蛋白乙酰转移酶（HAT）活性功能丧失相关的机制在神经元的寿命期间受损。几种HAT已被证明参与重要的神经元功能，如调节神经元可塑性和记忆形成。因此，这种HAT的失调已经涉及与年龄相关的神经退行性疾病和认知衰退相关的发病机制。为了抵消神经退行性疾病中HAT功能的丧失，目前的治疗策略涉及使用称为组蛋白脱乙酰酶（HDAC）抑制剂的小分子，其拮抗HDAC活性并因此提高乙酰化水平。虽然这种策略已经显示出有希望的治疗效果，但目前使用的HDAC抑制剂缺乏靶点特异性，引起了对其适用性的担忧。随着关于HAT及其各自在介导神经元存活和高阶脑功能（如学习和记忆）中的功能的文献的快速发展，调节特定HAT的功能作为神经退行性疾病的治疗工具具有新的前景。本文就神经元活动和认知功能的表观遗传组蛋白乙酰化机制的研究进展作一综述。我们讨论了目前对神经退行性疾病中特定HDAC和HAT的理解，以及使用基于特定HAT的治疗方法的未来前景。
Dynamic epigenetic regulation of neurons is emerging as a fundamental mechanism by which neurons adapt their transcriptional responses to specific developmental and environmental cues. While defects within the neural epigenome have traditionally been studied in the context of early developmental and heritable cognitive disorders, recent studies point to aberrant histone acetylation status as a key mechanism underlying acquired inappropriate alterations of genome structure and function in post-mitotic neurons during the aging process. Indeed, it is becoming increasingly evident that chromatin acetylation status can be impaired during the lifetime of neurons through mechanisms related to loss of function of histone acetyltransferase (HAT) activity. Several HATs have been shown to participate in vital neuronal functions such as regulation of neuronal plasticity and memory formation. As such, dysregulation of such HATs has been implicated in the pathogenesis associated with age-associated neurodegenerative diseases and cognitive decline. In order to counteract the loss of HAT function in neurodegenerative diseases, the current therapeutic strategies involve the use of small molecules called histone deacetylase (HDAC) inhibitors that antagonize HDAC activity and thus enhance acetylation levels. Although this strategy has displayed promising therapeutic effects, currently used HDAC inhibitors lack target specificity, raising concerns about their applicability. With rapidly evolving literature on HATs and their respective functions in mediating neuronal survival and higher order brain function such as learning and memory, modulating the function of specific HATs holds new promises as a therapeutic tool in neurodegenerative diseases. In this review, we focus on the recent progress in research regarding epigenetic histone acetylation mechanisms underlying neuronal activity and cognitive function. We discuss the current understanding of specific HDACs and HATs in neurodegenerative diseases and the future promising prospects of using specific HAT based therapeutic approaches.
登录
查看更多内容
DOI：
10.1523/jneurosci.0097-09.2009
发表时间：
2009-06-24
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Akhtar MW;Raingo J;Nelson ED;Montgomery RL;Olson EN;Kavalali ET;Monteggia LM
通讯作者：
Monteggia LM
DOI：
10.1073/pnas.1012851108
发表时间：
2010-12-28
影响因子：
11.1
作者：
Caccamo, Antonella;Maldonado, Monica A.;Oddo, Salvatore
通讯作者：
Oddo, Salvatore
影响因子：
56.9
作者：
Cao, XW;Südhof, TC
通讯作者：
Südhof, TC
影响因子：
5.1
作者：
Brady, Scott;Morfini, Gerardo
通讯作者：
Morfini, Gerardo
影响因子：
7.6
作者：
Barrett, Ruth M.;Malvaez, Melissa;Wood, Marcelo A.
通讯作者：
Wood, Marcelo A.