Induction of chemokines, MCP-1, and KC in the mutant huntingtin expressing neuronal cells because of proteasomal dysfunction
Induction of chemokines, MCP-1, and KC in the mutant huntingtin expressing neuronal cells because of proteasomal dysfunction
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DOI：
10.1111/j.1471-4159.2008.05823.x
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发表时间：
2009-02-01
影响因子：
4.7
通讯作者：
Jana, Nihar Ranjan
中科院分区：
文献类型：
--
作者：
Godavarthi, Swetha K.;Narender, Doronala;Jana, Nihar Ranjan
亨廷顿氏病是一种遗传性神经退行性疾病，由亨廷顿蛋白氨基末端异常聚谷氨酰胺扩张引起。由此产生的突变亨廷顿蛋白在神经元中形成聚集体，并以多种方式引起神经元功能障碍和变性，包括转录失调。在这里，我们报告突变亨廷顿蛋白在小鼠神经母细胞瘤细胞中的表达导致大量的转录诱导的几种趋化因子，包括单核细胞趋化蛋白-1（MCP-1）和小鼠趋化因子（KC）。表达突变亨廷顿蛋白的细胞还表现出蛋白酶体功能障碍和NF-κ B活性以时间依赖性方式下调，并且这两种现象都调节MCP-1和KC的表达。在表达突变亨廷顿蛋白的细胞中，MCP-1和KC的表达响应于轻度蛋白酶体抑制而增加。然而，MCP-1和KC的表达和蛋白酶体活性没有改变，并且在12周龄的亨廷顿病转基因小鼠的脑中与其年龄匹配的对照组相比很少观察到炎症。我们的研究结果表明，突变亨廷顿蛋白诱导的蛋白酶体功能障碍可以上调MCP-1和KC在神经细胞中的表达，因此可能触发炎症过程。
Huntington's disease is a hereditary neurodegenerative disorder caused by an aberrant polyglutamine expansion in the amino terminus of the huntingtin protein. The resultant mutant huntingtin form aggregates in neurons and causes neuronal dysfunction and degeneration in many ways including transcriptional dysregulation. Here, we report that the expression of mutant huntingtin in the mouse neuroblastoma cell results in massive transcriptional induction of several chemokines including monocyte chemoattractant protein-1 (MCP-1) and murine chemokine (KC). The mutant huntingtin expressing cells also exhibit proteasomal dysfunction and down-regulation of NF-kappa B activity in a time-dependent manner and both these phenomena regulate the expression of MCP-1 and KC. The expression of MCP-1 and KC are increased in the mutant huntingtin expressing cells in response to mild proteasome inhibition. However, the expression of MCP-1 and KC and proteasome activity are not altered and inflammation is rarely observed in the brain of 12-week-old Huntington's disease transgenic mice in comparison with their age-matched controls. Our result suggests that the mutant huntingtin-induced proteasomal dysfunction can up-regulate the expression of MCP-1 and KC in the neuronal cells and therefore might trigger the inflammation process.