Impaired glutamate transport and glutamate-glutamine cycling: downstream effects of the Huntington mutation
Impaired glutamate transport and glutamate-glutamine cycling: downstream effects of the Huntington mutation
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DOI：
10.1093/brain/awf180
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发表时间：
2002-08-01
期刊：
影响因子：
14.5
通讯作者：
Landwehrmeyer, G. B.
中科院分区：
文献类型：
--
作者：
Behrens, P. F.;Franz, P.;Landwehrmeyer, G. B.
亨廷顿病的发病机制至今仍不完全清楚。来自亨廷顿病的毒性/非转基因动物模型的几条证据表明，兴奋性毒性机制可能有助于病理表型。然而，来自亨廷顿病转基因动物模型的证据却很少。为了探索脑谷氨酸处理的潜在改变，我们研究了表达突变亨廷顿蛋白（R6/2）的N-末端片段的转基因小鼠。自由活动小鼠的脑内微透析也显示了类似的结果。R6/2和同窝对照的细胞外谷氨酸水平。然而，谷氨酸转运的L-反式-吡咯烷-2，4-二羧酸（4 mM）的部分抑制公开了与对照组相比，R6/2小鼠细胞外谷氨酸水平的年龄依赖性增加，与功能性谷氨酸转运能力的降低一致。生物化学研究表明，年龄依赖性下调的胶质细胞谷氨酸转运蛋白GLT-1的mRNA和蛋白质，导致在一个渐进的减少转运功能。除GLT-1外的谷氨酸转运蛋白未发生变化。此外，细胞外谷氨酰胺水平的增加和谷氨酰胺合成酶免疫反应性的改变表明谷氨酸-谷氨酰胺循环的扰动。这些发现表明，亨廷顿氏病突变导致大脑中谷氨酸处理逐渐紊乱，在小鼠症状发作之前就开始了。它们还提供了兴奋性毒性对亨廷顿病的病理生理学的贡献的证据，因此亨廷顿病可能被添加到与受损的谷氨酸转运能力相关的神经退行性疾病的不断增长的列表中。
The pathogenesis of Huntington's disease is still not completely understood. Several lines of evidence from toxic/non-transgenic animal models of Huntington's disease suggest that excitotoxic mechanisms may contribute to the pathological phenotype. Evidence from transgenic animal models of Huntington's disease, however, is sparse. To explore potential alterations in brain glutamate handling we studied transgenic mice expressing an N-terminal fragment of mutant huntingtin (R6/2). Intracerebral microdialysis in freely moving mice showed similar. extracellular glutamate levels in R6/2 and littermate controls. However, partial inhibition of glutamate transport by L-trans-pyrrolidine-2,4-dicarboxylate (4 mM) disclosed an age-dependent increase in extracellular glutamate levels in R6/2 mice compared with controls, consistent with a reduction of functional glutamate transport capacity. Biochemical studies demonstrated an age-dependent downregulation of the glial glutamate transporter GLT-1 mRNA and protein, resulting in a progressive reduction of transporter function. Glutamate transporters other than GLT-1 were unchanged. In addition, increased extracellular glutamine levels and alterations to glutamine synthetase immunoreactivity suggested a perturbation of the glutamate-glutamine cycle. These findings demonstrate that the Huntington's disease mutation results in a progressively deranged glutamate handling in the brain, beginning before the onset of symptoms in mice. They also provide evidence for a contribution of excitotoxicity to the pathophysiology of Huntington's disease, and thus Huntington's disease may be added to the growing list of neurodegenerative disorders associated with compromised glutamate transport capacity.