CEP-1347 reduces mutant huntingtin-associated neurotoxicity and restores BDNF levels in R6/2 mice
CEP-1347 reduces mutant huntingtin-associated neurotoxicity and restores BDNF levels in R6/2 mice
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DOI：
10.1016/j.mcn.2008.04.007
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发表时间：
2008-09-01
影响因子：
3.5
通讯作者：
Thompson, Leslie Michels
中科院分区：
文献类型：
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作者：
Apostol, Barbara L.;Simmons, Danielle A.;Thompson, Leslie Michels
亨廷顿病（HD）是由亨廷顿蛋白（Htt）内的多聚谷氨酰胺重复序列扩增引起的破坏性神经退行性疾病。我们先前报道了突变型Htt表达激活ERK 1/2和JNK途径[Apostol，B.L.，Illes，K.，Pallos，J.，博代湖吴，J.，Strand，A.，Schweitzer，E.S.，奥尔森，J. M.，Kazantsev，A.，Marsh，J.L.，Thompson，L.M.，2006.突变亨廷顿蛋白改变PC 1/2和纹状体细胞中的MAPK信号通路：ERK 1/2保护免受突变亨廷顿蛋白相关毒性Hum.摩尔Genet. 15，273-285]。这些途径的化学和遗传调节分别促进细胞存活和死亡。在这里，我们测试了两种密切相关的化合物CEP-11004和CEP-1347在多个模型系统中抑制突变型Htt介导的发病机制的能力，这两种化合物抑制混合谱系激酶（MLK）并且具有神经保护作用。CEP-11004/CEP-1347处理显著降低了引起强烈JNK应答的突变型Htt表达细胞中的毒性。然而，抑制细胞功能障碍的细胞系，表现出只有轻微的Htt相关的毒性和JNK激活很少与ERK 1/2的激活。这些化合物还降低了来自突变体敲入小鼠和表达突变体Htt片段的果蝇的永生化纹状体神经元中的神经毒性。最后，CEP-1347改善了R6/2小鼠的运动表现，并恢复了BDNF的表达，BDNF是一种在HID中减少的关键神经营养因子。这些研究表明，通过CEP-1347上调BDNF，为目前无法治疗的神经退行性疾病HD提供了一种新的治疗方法。(C)2008年爱思唯尔公司All rights reserved.
Huntington's disease (HD) is a devastating neurodegenerative disorder caused by an expanded polyglutamine repeat within the protein Huntingtin (Htt). We previously reported that mutant Htt expression activates the ERK1/2 and JNK pathways [Apostol, B.L., Illes, K., Pallos, J., Bodai, L., Wu, J., Strand, A., Schweitzer, E.S., Olson, J.M., Kazantsev, A., Marsh,J.L, Thompson, L.M., 2006. Mutant huntingtin alters MAPK signaling pathways in PC12 and striatal cells: ERK1/2 protects against mutant huntingtin-associated toxicity. Hum. Mol. Genet. 15, 273-285]. Chemical and genetic modulation of these pathways promotes cell survival and death, respectively. Here we test the ability of two closely related compounds, CEP-11004 and CEP-1347, which inhibit Mixed Lineage Kinases (MLKs) and are neuro protective, to suppress mutant Htt-mediated pathogenesis in multiple model systems. CEP-11004/CEP-1347 treatment significantly decreased toxicity in mutant Htt-expressing cells that evoke a strong JNK response. However, suppression of cellular dysfunction in cell lines that exhibit only mild Htt-associated toxicity and little JNK activation was associated with activation of ERK1/2. These compounds also reduced neurotoxicity in immortalized striatal neurons from Mutant knock-in mice and Drosophila expressing a mutant Htt fragment. Finally, CEP-1347 improved motor performance in R6/2 mice and restored expression of BDNF, a critical neurotrophic factor that is reduced in HID. These studies suggest a novel therapeutic approach for a currently untreatable neurodegenerative disease, HD, via CEP-1347 up-regulation of BDNF. (C) 2008 Elsevier Inc. All rights reserved.