Identification of anti-inflammatory targets for Huntington's disease using a brain slice-based screening assay.
Identification of anti-inflammatory targets for Huntington's disease using a brain slice-based screening assay.
复制标题
使用基于脑切片的筛选测定来鉴定亨廷顿病的抗炎靶标。
DOI：
10.1016/j.nbd.2011.03.017
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发表时间：
2011
影响因子：
6.1
通讯作者：
Lo,DonaldC
中科院分区：
文献类型：
--
作者：
Reinhart,PeterH;Kaltenbach,LindaS;Essrich,Christian;Dunn,DeniseE;Eudailey,JoshuaA;DeMarco,CTodd;Turmel,GregoryJ;Whaley,JenniferC;Wood,Andrew;Cho,Seongeun;Lo,DonaldC
亨廷顿氏病（HD）是一种迟发性神经退行性疾病，目前对其没有治愈方法或改善疾病的治疗方法。在这里，我们报告了几个潜在的抗炎目标HD使用anex vivomodel的HD，涉及急性转染的人突变亨廷顿蛋白为基础的结构到大鼠脑切片。该模型概括了人类疾病的关键组成部分，包括细胞内含有亨廷顿蛋白（HTT）的包涵体的形成和纹状体神经元的进行性神经变性-两者都发生在这些神经元的天然组织环境中。使用这种“高通量生物学”筛选平台，我们对一系列药物样化合物进行了假设中性筛选，这些药物样化合物鉴定了几种抗炎靶点，这些靶点提供了针对HTT片段诱导的神经变性的神经保护。这些目标的性质提供了进一步的支持非细胞自主机制介导的突变HTT片段蛋白诱导的神经发病机制的重要方面。
Huntington's disease (HD) is a late-onset, neurodegenerative disease for which there are currently no cures nor disease-modifying treatments. Here we report the identification of several potential anti-inflammatory targets for HD using anex vivomodel of HD that involves the acute transfection of human mutant huntingtin-based constructs into rat brain slices. This model recapitulates key components of the human disease, including the formation of intracellular huntingtin protein (HTT)-containing inclusions and the progressive neurodegeneration of striatal neurons—both occurring within the native tissue context of these neurons. Using this “high-throughput biology” screening platform, we conducted a hypothesis-neutral screen of a collection of drug-like compounds which identified several anti-inflammatory targets that provided neuroprotection against HTT fragment-induced neurodegeneration. The nature of these targets provide further support for non-cell autonomous mechanisms mediating significant aspects of neuropathogenesis induced by mutant HTT fragment proteins.