Giorgini Flaviano, Möller Thomas, Kwan Wanda, Zwilling Daniel, Wacker Jennifer L, Hong Soyon, Tsai Li-Chun L, Cheah Christine S, Schwarcz Robert, Guidetti Paolo, Muchowski Paul J
Department of Pharmacology, University of Washington, Seattle, Washington 98195, USA.
J Biol Chem. 2008 Mar 21;283(12):7390-400. doi: 10.1074/jbc.M708192200. Epub 2007 Dec 13.
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.
色氨酸降解的犬尿氨酸途径被认为在亨廷顿病中起重要作用，亨廷顿病是一种由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。在疾病早期，由小胶质细胞和巨噬细胞产生的犬尿氨酸途径的神经毒性代谢产物在患者和小鼠模型大脑中的水平升高，但犬尿氨酸途径在亨廷顿病中上调的机制尚不清楚。在此，我们报告突变型亨廷顿片段的表达足以在酵母中诱导犬尿氨酸途径的转录，并且这种诱导通过损害组蛋白脱乙酰酶Rpd3的活性而被消除。此外许多功能上不相关的突变型亨廷顿毒性的遗传抑制因子意外地汇聚在犬尿氨酸途径上，这支持了犬尿氨酸途径在介导酵母中突变型亨廷顿毒性方面的关键作用。在亨廷顿病的小鼠模型中也观察到了组蛋白脱乙酰酶依赖性的犬尿氨酸途径调节，其中用神经保护性组蛋白脱乙酰酶抑制剂进行治疗可在体外和体内阻断表达突变型亨廷顿片段的小胶质细胞中犬尿氨酸途径的激活。这些发现表明，突变型亨廷顿片段可扰乱小胶质细胞中的转录程序，从而表明这些细胞是亨廷顿病中神经退行性变的潜在调节因子，值得进一步研究。
