Zeron Melinda M, Fernandes Herman B, Krebs Claudia, Shehadeh Jacqueline, Wellington Cheryl L, Leavitt Blair R, Baimbridge Kenneth G, Hayden Michael R, Raymond Lynn A
Kinsmen Laboratory of Neurological Research, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
Mol Cell Neurosci. 2004 Mar;25(3):469-79. doi: 10.1016/j.mcn.2003.11.014.
Evidence suggests N-methyl-D-aspartate receptor (NMDAR) activation is involved in the degeneration of striatal medium-sized spiny neurons (MSNs) in Huntington's disease (HD). We tested the hypothesis that enhanced NMDAR-mediated excitotoxicity is mediated by the mitochondrial-associated apoptotic pathway in cultured MSNs from YAC transgenic mice expressing full-length huntingtin (htt) with a polyglutamine (polyQ) expansion of 46 or 72 (YAC46 or YAC72). NMDAR-mediated Ca(2+) transients and mitochondrial membrane depolarization were significantly increased in YAC compared to wild-type mice MSNs. Inhibitors of the mitochondrial permeability transition (mPT), cyclosporin A and bongkrekic acid, and coenzyme Q10 (an anti-oxidant involved in bioenergetic metabolism) dramatically diminished NMDA-induced cell death and eliminated genotypic differences. In YAC46 MSNs, NMDA stimulated significantly higher activation of caspase-3 and caspase-9 but not caspase-8, and NMDA-induced caspase-3 and -9 activation was markedly attenuated by cyclosporin A. Agents that improve mitochondrial function or inhibit the permeability transition may eliminate increased caspase activation and cell death associated with enhanced NMDAR activity in HD.
有证据表明，N-甲基-D-天冬氨酸受体（NMDAR）激活参与了亨廷顿舞蹈病（HD）中纹状体中等大小多棘神经元（MSN）的退化。我们测试了这样一个假设：在表达全长亨廷顿蛋白（htt）且聚谷氨酰胺（polyQ）扩展为46或72（YAC46或YAC72）的YAC转基因小鼠的培养MSN中，增强的NMDAR介导的兴奋性毒性是由线粒体相关的凋亡途径介导的。与野生型小鼠的MSN相比，YAC小鼠的MSN中NMDAR介导的Ca(2+)瞬变和线粒体膜去极化显著增加。线粒体通透性转换（mPT）抑制剂环孢菌素A和硼酸，以及辅酶Q10（一种参与生物能量代谢的抗氧化剂）显著减少了NMDA诱导的细胞死亡并消除了基因型差异。在YAC46 MSN中，NMDA刺激caspase-3和caspase-9的激活显著更高，但不刺激caspase-8，并且环孢菌素A显著减弱了NMDA诱导的caspase-3和-9激活。改善线粒体功能或抑制通透性转换的药物可能消除与HD中增强的NMDAR活性相关的caspase激活增加和细胞死亡。
