An epigenetic blockade of cognitive functions in the neurodegenerating brain.
An epigenetic blockade of cognitive functions in the neurodegenerating brain.
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神经退行性大脑中认知功能的表观遗传封锁
DOI：
10.1038/nature10849
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发表时间：
2012-02-29
期刊：
影响因子：
64.8
通讯作者：
Tsai, Li-Huei
中科院分区：
文献类型：
--
作者：
Graeff, Johannes;Rei, Damien;Guan, Ji-Song;Wang, Wen-Yuan;Seo, Jinsoo;Hennig, Krista M.;Nieland, Thomas J. F.;Fass, Daniel M.;Kao, Patricia F.;Kahn, Martin;Su, Susan C.;Samiei, Alireza;Joseph, Nadine;Haggarty, Stephen J.;Delalle, Ivana;Tsai, Li-Huei
认知能力下降是包括阿尔茨海默病（AD）在内的大多数中枢神经系统神经退行性疾病的衰弱特征。导致这种损害的原因知之甚少，有效的治疗方法出现缓慢。在这里，我们表明，在神经退行性大脑的认知能力受到基因转录的表观遗传阻滞，这是潜在的可逆性。这种阻断是由组蛋白去乙酰化酶（HDAC）2介导的，在两种神经退行性小鼠模型和AD患者中，组蛋白去乙酰化酶2在体外AD相关神经毒性损伤中增加。HDAC2与对学习和记忆重要的基因的组蛋白乙酰化相关并减少其乙酰化，这显示伴随的表达减少。重要的是，通过shRNA介导的敲低逆转HDAC2的积累，可以解锁这些基因的抑制，恢复结构和突触可塑性，并消除神经退行性相关的记忆障碍。这些发现提倡开发HDAC2选择性抑制剂，并表明神经退行性变后的认知能力并没有完全丧失，而只是受到这种表观遗传阻断的损害。
Cognitive decline is a debilitating feature of most neurodegenerative diseases of the central nervous system, including Alzheimer’s disease (AD). The causes leading to such impairment are only poorly understood and effective treatments are slow to emerge. Here, we show that cognitive capacities in the neurodegenerating brain are constrained by an epigenetic blockade of gene transcription that is potentially reversible. This blockade is mediated by histone deacetylase (HDAC) 2, which is increased by AD-related neurotoxic insults in vitro, in two mouse models of neurodegeneration, and in AD patients. HDAC2 associates with and reduces the histone acetylation of genes important for learning and memory, which show a concomitant decrease in expression. Importantly, reversing the buildup of HDAC2 by shRNA-mediated knockdown unlocks the repression of these genes, re-instates structural and synaptic plasticity, and abolishes neurodegeneration-associated memory impairments. These findings advocate for the development of HDAC2-selective inhibitors, and suggest that cognitive capacities following neurodegeneration are not entirely lost, but merely impaired by this epigenetic blockade.
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影响因子：
4
作者：
Brownell, JE;Allis, CD
通讯作者：
Allis, CD
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
影响因子：
25
作者：
Palop, Jorge J.;Mucke, Lennart
通讯作者：
Mucke, Lennart
影响因子：
16.2
作者：
Fischer, A;Sananbenesi, F;Tsai, LH
通讯作者：
Tsai, LH
影响因子：
16.2
作者：
Cruz, JC;Tseng, HC;Tsai, LH
通讯作者：
Tsai, LH