Histone deacetylase inhibition modulates kynurenine pathway activation in yeast, microglia, and mice expressing a mutant huntingtin fragment
Histone deacetylase inhibition modulates kynurenine pathway activation in yeast, microglia, and mice expressing a mutant huntingtin fragment
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DOI：
10.1074/jbc.m708192200
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发表时间：
2008-03-21
影响因子：
4.8
通讯作者：
Muchowski, Paul J.
中科院分区：
文献类型：
--
作者：
Giorgini, Flaviano;Moller, Thomas;Muchowski, Paul J.
色氨酸降解的犬尿氨酸途径被假设在亨廷顿病中起重要作用，亨廷顿病是由蛋白亨廷顿蛋白中的多聚谷氨酰胺扩增引起的神经退行性疾病。在疾病的早期阶段，在小胶质细胞和巨噬细胞中产生的犬尿氨酸途径的神经毒性代谢物以增加的水平存在于患者和小鼠模型的脑中，但在亨廷顿病中发生犬尿氨酸途径上调的机制尚不清楚。在这里，我们报告的突变亨廷顿蛋白片段的表达是足以诱导在酵母中的犬尿氨酸途径的转录，这种诱导被废除的组蛋白脱乙酰酶Rpd3的活性受损。此外，功能上不相关的突变亨廷顿蛋白毒性的许多遗传抑制因子意外地聚集在犬尿氨酸途径上，支持犬尿氨酸途径在酵母中介导突变亨廷顿蛋白毒性中的关键作用。在亨廷顿病的小鼠模型中也观察到犬尿氨酸途径的组蛋白脱乙酰酶依赖性调节，其中用神经保护性组蛋白脱乙酰酶抑制剂治疗在体外和体内阻断表达突变亨廷顿片段的小胶质细胞中犬尿氨酸途径的活化。这些发现表明突变的亨廷顿蛋白片段可以扰乱小胶质细胞中的转录程序，从而暗示这些细胞作为亨廷顿病中神经变性的潜在调节剂，值得进一步研究。
The kynurenine pathway of tryptophan degradation is hypothesized to play an important role in Huntington disease, a neurodegenerative disorder caused by a polyglutamine expansion in the protein huntingtin. Neurotoxic metabolites of the kynurenine pathway, generated in microglia and macrophages, are present at increased levels in the brains of patients and mouse models during early stages of disease, but the mechanism by which kynurenine pathway up-regulation occurs in Huntington disease is unknown. Here we report that expression of a mutant huntingtin fragment was sufficient to induce transcription of the kynurenine pathway in yeast and that this induction was abrogated by impairing the activity of the histone deacetylase Rpd3. Moreover, numerous genetic suppressors of mutant huntingtin toxicity that are functionally unrelated converged unexpectedly on the kynurenine pathway, supporting a critical role for the kynurenine pathway in mediating mutant huntingtin toxicity in yeast. Histone deacetylase-dependent regulation of the kynurenine pathway was also observed in a mouse model of Huntington disease, in which treatment with a neuroprotective histone deacetylase inhibitor blocked activation of the kynurenine pathway in microglia expressing a mutant huntingtin fragment in vitro and in vivo. These findings suggest that a mutant huntingtin fragment can perturb transcriptional programs in microglia, and thus implicate these cells as potential modulators of neurodegeneration in Huntington disease that are worthy of further investigation.