The Effects of Pharmacological Inhibition of Histone Deacetylase 3 (HDAC3) in Huntington's Disease Mice.
The Effects of Pharmacological Inhibition of Histone Deacetylase 3 (HDAC3) in Huntington's Disease Mice.
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DOI：
10.1371/journal.pone.0152498
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Thomas EA
中科院分区：
文献类型：
--
作者：
Jia H;Wang Y;Morris CD;Jacques V;Gottesfeld JM;Rusche JR;Thomas EA
组蛋白乙酰化是亨廷顿病（HD）研究中一个重要的表观遗传修饰，它受组蛋白乙酰转移酶和组蛋白去乙酰化酶（HDAC）的调控。HDAC抑制剂已被证明在HD模型系统中有效，并且最近的工作现在集中于在这些作用中对个体HDAC酶的功能解剖。组蛋白去乙酰化酶3（HDAC 3）是HDAC的I类亚家族的成员，先前已涉及神经元毒性和亨廷顿蛋白诱导的细胞死亡。因此，我们在HD的N171- 82 Q转基因小鼠模型中检测了RGFP 966（（E）-N-（2-氨基-4-氟苯基）-3-（1-肉桂基-1H-吡唑-4-基）丙烯酰胺）（一种选择性靶向HDAC 3的苯甲酰胺型HDAC抑制剂）的作用。我们发现，10和25 mg/kg剂量的RGFP 966改善了旋转棒和开放视野探索中的运动缺陷，并伴有对纹状体体积的神经保护作用。鉴于先前的研究表明HDAC 3与免疫功能有关，我们使用定量PCR阵列测量了RGFP 966引起的84个免疫相关基因的基因表达变化。在N171- 82 Q转基因小鼠（但非WT小鼠）中，RGFP 966处理未引起细胞因子/趋化因子基因表达模式的广泛变化，但显著改变了巨噬细胞迁移抑制因子（Mif）（一种与神经胶质细胞活化相关的激素免疫调节剂）的纹状体表达。因此，与溶媒给药小鼠相比，RGFP 966给药小鼠显示N171- 82 Q转基因小鼠纹状体中胶质细胞酸性蛋白（GFAP）免疫反应性（星形胶质细胞活化的标志物）降低。这些发现表明HDAC 3抑制的有益作用可能部分与降低的Mif水平及其相关的下游效应有关。
An important epigenetic modification in Huntington’s disease (HD) research is histone acetylation, which is regulated by histone acetyltransferase and histone deacetylase (HDAC) enzymes. HDAC inhibitors have proven effective in HD model systems, and recent work is now focused on functional dissection of the individual HDAC enzymes in these effects. Histone deacetylase 3 (HDAC3), a member of the class I subfamily of HDACs, has previously been implicated in neuronal toxicity and huntingtin-induced cell death. Hence, we tested the effects of RGFP966 ((E)-N-(2-amino-4-fluorophenyl)-3-(1-cinnamyl-1H-pyrazol-4-yl)acrylamide), a benzamide-type HDAC inhibitor that selectively targets HDAC3, in the N171-82Q transgenic mouse model of HD. We found that RGFP966 at doses of 10 and 25 mg/kg improves motor deficits on rotarod and in open field exploration, accompanied by neuroprotective effects on striatal volume. In light of previous studies implicating HDAC3 in immune function, we measured gene expression changes for 84 immune-related genes elicited by RGFP966 using quantitative PCR arrays. RGFP966 treatment did not cause widespread changes in cytokine/chemokine gene expression patterns, but did significantly alter the striatal expression of macrophage migration inhibitory factor (Mif), a hormone immune modulator associated with glial cell activation, in N171-82Q transgenic mice, but not WT mice. Accordingly, RGFP966-treated mice showed decreased glial fibrillary acidic protein (GFAP) immunoreactivity, a marker of astrocyte activation, in the striatum of N171-82Q transgenic mice compared to vehicle-treated mice. These findings suggest that the beneficial actions of HDAC3 inhibition could be related, in part, with lowered Mif levels and its associated downstream effects.