Shehadeh Jacqueline, Fernandes Herman B, Zeron Mullins Melinda M, Graham Rona K, Leavitt Blair R, Hayden Michael R, Raymond Lynn A
Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada.
Neurobiol Dis. 2006 Feb;21(2):392-403. doi: 10.1016/j.nbd.2005.08.001. Epub 2005 Sep 13.
Huntington disease (HD), caused by expansion >35 of a polyglutamine tract in huntingtin, results in degeneration of striatal medium spiny neurons (MSNs). Previous studies demonstrated mitochondrial dysfunction, altered intracellular calcium release, and enhanced NMDAR-mediated current and apoptosis in cellular and mouse models of HD. Here, we exposed cultured MSNs from YAC transgenic mice, expressing full-length human huntingtin with 18, 72, or 128 repeats, to a variety of apoptosis-inducing compounds that inhibit mitochondrial function or increase intracellular calcium, and assessed apoptosis 24 h later. All compounds produced a polyglutamine length-dependent increase in apoptosis, but NMDA produced the largest potentiation in apoptosis of YAC72 and YAC128 versus YAC18 MSNs. Moreover, reduction of NMDAR-mediated current and calcium influx in YAC72 MSNs to levels seen in wild-type reduced NMDAR-mediated apoptosis proportionately to wild-type levels. Our results suggest that increased NMDAR signaling plays a major role in enhanced excitotoxic MSN death in this HD mouse model.
亨廷顿舞蹈症（HD）由亨廷素中多聚谷氨酰胺序列超过35个重复扩增引起，导致纹状体中等棘状神经元（MSN）退化。先前的研究在HD细胞和小鼠模型中证实了线粒体功能障碍、细胞内钙释放改变、NMDAR介导的电流增强以及细胞凋亡。在此，我们将表达含18、72或128个重复序列的全长人类亨廷素的YAC转基因小鼠的培养MSN暴露于多种抑制线粒体功能或增加细胞内钙的凋亡诱导化合物中，并在24小时后评估细胞凋亡情况。所有化合物均使细胞凋亡呈多聚谷氨酰胺长度依赖性增加，但与YAC18 MSN相比，NMDA对YAC72和YAC128 MSN的凋亡具有最大的增强作用。此外，将YAC72 MSN中NMDAR介导的电流和钙内流降低至野生型水平，可使NMDAR介导的凋亡相应降低至野生型水平。我们的结果表明，在该HD小鼠模型中，增强的NMDAR信号在兴奋性毒性MSN死亡增加中起主要作用。
