Effects of Mutant Huntingtin on mGluR5-Mediated Dual Signaling Pathways: Implications for Therapeutic Interventions
Effects of Mutant Huntingtin on mGluR5-Mediated Dual Signaling Pathways: Implications for Therapeutic Interventions
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突变亨廷顿蛋白对 mGluR5 介导的双重信号通路的影响：对治疗干预的影响
DOI：
10.1007/s10571-010-9543-7
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发表时间：
2010-10-01
影响因子：
4
通讯作者：
Li, He
中科院分区：
文献类型：
--
作者：
Huang, Shan-Shan;He, Jun;Li, He
谷氨酸兴奋毒性被认为在亨廷顿病（HD）中起重要作用，其由HD蛋白亨廷顿蛋白（htt）中的多聚谷氨酰胺扩增引起。I组代谢型谷氨酸受体（mGluRs），其中包括mGluR1以及mGluR5和耦合通过磷脂酶C的磷酸肌醇途径，被发现参与突变体HT介导的神经毒性。然而，mGluR5的激活也导致神经元保护。在这里，我们报告突变htt可以激活mGluR5介导的ERK和JNK信号通路。虽然增加的JNK信号传导导致细胞死亡，但ERK信号传导途径的激活对细胞死亡具有保护作用。突变htt在培养细胞中的表达引起JNK比ERK更大的激活。这些发现表明，选择性抑制JNK信号通路可能提供一种有效的治疗方法，减少HT介导的兴奋性毒性。
Glutamate excitotoxicity is thought to play an important role in Huntington's disease (HD), which is caused by a polyglutamine expansion in the HD protein huntingtin (htt). Overactivation of group I metabotropic glutamate receptors (mGluRs), which include mGluR1 as well as mGluR5 and are coupled via phospholipase C to the inositol phosphate pathway, is found to be involved in mutant htt-mediated neurotoxicity. However, activation of mGluR5 also leads to neuronal protection. Here, we report that mutant htt can activate both mGluR5-mediated ERK and JNK signaling pathways. While increased JNK signaling causes cell death, activation of ERK signaling pathway is protective against cell death. Expression of mutant htt in cultured cells causes greater activation of JNK than ERK. These findings suggest that selective inhibition of the JNK signaling pathway may offer an effective therapeutic approach for reducing htt-mediated excitotoxicity.