• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Journal of Neurochemistry: Offical Journal of the International Society for Neurochemistry >Alterations in STriatal-Enriched protein tyrosine Phosphatase expression, activation, and downstream signaling in early and late stages of the YAC128 Huntington's disease mouse model
【24h】

Alterations in STriatal-Enriched protein tyrosine Phosphatase expression, activation, and downstream signaling in early and late stages of the YAC128 Huntington's disease mouse model

机译：YAC128亨廷顿氏病小鼠模型早期和晚期富含结构蛋白的蛋白酪氨酸磷酸酶表达，激活和下游信号转导的变化

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Striatal neurodegeneration and synaptic dysfunction in Huntington's disease are mediated by the mutant huntingtin (mHtt) protein. MHtt disrupts calcium homeostasis and facilitates excitotoxicity, in part by altering NMDA receptor (NMDAR) trafficking and function. Pre-symptomatic (excitotoxin-sensitive) transgenic mice expressing full-length human mHtt with 128 polyglutamine repeats (YAC128 Huntington's disease mice) show increased calpain activity and extrasynaptic NMDAR (Ex-NMDAR) localization and signaling. Furthermore, Ex-NMDAR stimulation facilitates excitotoxicity in wild-type cortical neurons via calpain-mediated cleavage of STriatal-Enriched protein tyrosine Phosphatase 61 (STEP61). The cleavage product, STEP33, cannot dephosphorylate p38 mitogen-activated protein kinase (MAPK), thereby augmenting apoptotic signaling. Here, we show elevated extrasynaptic calpain-mediated cleavage of STEP61 and p38 phosphorylation, as well as STEP61 inactivation and reduced extracellular signal-regulated protein kinase 1/2 phosphorylation (ERK1/2) in the striatum of 6-week-old, excitotoxin-sensitive YAC128 mice. Calpain inhibition reduced basal and NMDA-induced STEP61 cleavage. However, basal p38 phosphorylation was normalized by a peptide disrupting NMDAR-post-synaptic density protein-95 (PSD-95) binding but not by calpain inhibition. In 1-year-old excitotoxin-resistant YAC128 mice, STEP33 levels were not elevated, but STEP61 inactivation and p38 and ERK 1/2 phosphorylation levels were increased. These results show that in YAC128 striatal tissue, enhanced NMDAR-PSD-95 interactions contributes to elevated p38 signaling in early, excitotoxin-sensitive stages, and suggest that STEP61 inactivation enhances MAPK signaling at late, excitotoxin-resistant stages. The YAC128 Huntington's disease mouse model shows early, enhanced susceptibility to NMDA receptor-mediated striatal apoptosis, progressing to late-stage excitotoxicity resistance. This study shows that elevated NMDA receptor-PSD-95 interactions as well as decreased extrasynaptic STriatal-Enriched protein tyrosine Phosphatase 61 (STEP61) activation may contribute to early enhanced apoptotic signaling. In late-stage YAC128 mice, reduced STEP61 levels and activity correlate with elevated MAPK signaling, consistent with excitotoxicity resistance. Solid and dotted arrows indicate conclusions drawn from the current study and other literature, respectively.
机译：亨廷顿氏病中的纹状体神经变性和突触功能障碍是由突变的亨廷顿蛋白（mHtt）介导的。 MHtt部分地通过改变NMDA受体（NMDAR）的运输和功能来破坏钙的动态平衡并促进兴奋性毒性。表达具有128个聚谷氨酰胺重复序列的全长人类mHtt的症状前（兴奋毒素敏感）转基因小鼠（YAC128亨廷顿舞蹈病小鼠）显示出钙蛋白酶活性增加和突触外NMDAR（Ex-NMDAR）定位和信号传导。此外，Ex-NMDAR刺激通过钙蛋白酶介导的富含STRATAL的蛋白酪氨酸磷酸酶61（STEP61）的裂解，促进野生型皮质神经元的兴奋性毒性。裂解产物STEP33不能使p38丝裂原激活的蛋白激酶（MAPK）脱磷酸化，从而增强凋亡信号。在这里，我们显示了6周龄的兴奋性毒素-纹状体中突触外钙蛋白酶介导的STEP61和p38磷酸化裂解，以及STEP61失活和细胞外信号调节蛋白激酶1/2磷酸化（ERK1 / 2）减少。敏感的YAC128小鼠。钙蛋白酶抑制减少基础和NMDA诱导的STEP61裂解。但是，基础p38磷酸化是通过破坏NMDAR突触后密度蛋白95（PSD-95）结合的肽而不是钙蛋白酶抑制作用来标准化的。在1岁的抗兴奋毒素的YAC128小鼠中，STEP33的水平没有升高，但是STEP61的失活以及p38和ERK 1/2的磷酸化水平增加了。这些结果表明，在YAC128纹状体组织中，增强的NMDAR-PSD-95相互作用增强了对兴奋性毒素敏感的早期阶段中p38信号的升高，并表明STEP61失活增强了抗兴奋性毒素晚期的MAPK信号通路。 YAC128亨廷顿舞蹈病小鼠模型显示出对NMDA受体介导的纹状体细胞凋亡的早期增强的敏感性，发展为晚期兴奋性毒性抵抗。这项研究表明，NMDA受体-PSD-95相互作用的增强以及突触后富含STRatal的蛋白酪氨酸磷酸酶61（STEP61）的激活减少可能有助于早期增强凋亡信号。在晚期YAC128小鼠中，降低的STEP61水平和活性与升高的MAPK信号传导相关，这与抗兴奋性毒性相一致。实线和虚线箭头分别表示从当前研究和其他文献得出的结论。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号