Department of Biochemistry and Molecular Biology, University of Szeged, Szeged, Hungary.
Bioessays. 2012 Feb;34(2):142-8. doi: 10.1002/bies.201100116.
Activating the ERK pathway (extracellular signal-regulated kinase pathway) has proven beneficial in several models of Huntington's disease (HD), and drugs that are protective in HD models have recently been found to activate ERK. Thus, the ERK cascade may be a potential target for therapeutic intervention in this currently untreatable disorder. HD is caused by an expanded polyglutamine repeat in the huntingtin (Htt) protein that actuates a diverse set of pathogenic mechanisms. In response to mutant Htt, ERK is activated and directs a protective transcriptional response and inhibits caspase activation. Paradoxically, Htt also interferes with several signaling events of the ERK pathway. Mutant Htt compromises the ERK-dependent transcriptional response to corticostriatal BDNF signaling. Mutant Htt also hinders glutamate uptake from the synaptic cleft by down-regulating ERK-dependent expression of glutamate transporters, leaving cells vulnerable to excitotoxicity. Some of this cellular complexity can be capitalized on to achieve selective activation of ERK, which can be protective.
激活细胞外信号调节激酶通路（ERK 通路）已被证明对几种亨廷顿病（HD）模型有益，而最近发现对 HD 模型具有保护作用的药物可激活 ERK。因此，ERK 级联反应可能是治疗目前无法治疗的疾病的潜在靶点。HD 是由亨廷顿蛋白（Htt）中扩展的多聚谷氨酰胺重复引起的，该蛋白激活了多种致病机制。响应突变的 Htt，ERK 被激活并指导保护性转录反应并抑制半胱天冬酶的激活。矛盾的是，Htt 还干扰 ERK 通路的几个信号事件。突变的 Htt 损害了皮质纹状体 BDNF 信号对 ERK 依赖性转录反应。突变的 Htt 还通过下调 ERK 依赖性谷氨酸转运体的表达，阻碍谷氨酸从突触间隙摄取，使细胞易受兴奋性毒性影响。可以利用这种细胞复杂性来实现对 ERK 的选择性激活，这可能具有保护作用。
