Selective deficits in the expression of striatal-enriched mRNAs in Huntington's disease
Selective deficits in the expression of striatal-enriched mRNAs in Huntington's disease
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DOI：
10.1111/j.1471-4159.2005.03588.x
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发表时间：
2006-02-01
影响因子：
4.7
通讯作者：
Thomas, EA
中科院分区：
文献类型：
--
作者：
Desplats, PA;Kass, KE;Thomas, EA
我们已经确定并编目了54个在纹状体中主要表达的基因。我们的假设是，这种mRNA分子可能编码优先与纹状体神经元固有的特定生理过程相关的蛋白质，因此可能有助于在亨廷顿病(HD)等纹状体疾病中观察到的神经变性的区域性特异性。用Affymetrix寡核苷酸芯片同时检测这些基因在HD R6/1转基因小鼠纹状体内的表达。我们发现，在HD转基因小鼠中，81%的纹状体丰富基因的表达减少。与G蛋白信号和钙稳态相关的基因表达的变化是突出的。最显著的是观察到新发现的钠通道亚单位β4的表达减少，从8周开始表达急剧减少。用实时定量聚合酶链式反应检测HD患者尾状核样本中的纹状体基因亚集。在人类HD和所测试的纹状体基因的R6/1模型中也观察到了类似的表达变化。在6-羟基多巴胺损伤的大鼠中，测量了15个纹状体丰富基因的表达，以确定它们对多巴胺神经支配的依赖性。没有观察到这些基因的表达变化。这些发现表明，突变的Huntingtin蛋白导致负责纹状体特异生理的mRNAs表达选择性缺失，这可能有助于HD观察到的变性的区域特异性。
We have identified and cataloged 54 genes that exhibit predominant expression in the striatum. Our hypothesis is that such mRNA molecules are likely to encode proteins that are preferentially associated with particular physiological processes intrinsic to striatal neurons, and therefore might contribute to the regional specificity of neurodegeneration observed in striatal disorders such as Huntington's disease (HD). Expression of these genes was measured simultaneously in the striatum of HD R6/1 transgenic mice using Affymetrix oligonucleotide arrays. We found a decrease in expression of 81% of striatum-enriched genes in HD transgenic mice. Changes in expression of genes associated with G-protein signaling and calcium homeostasis were highlighted. The most striking decrement was observed for a newly identified subunit of the sodium channel, beta 4, with dramatic decreases in expression beginning at 8 weeks of age. A subset of striatal genes was tested by real-time PCR in caudate samples from human HD patients. Similar alterations in expression were observed in human HD and the R6/1 model for the striatal genes tested. Expression of 15 of the striatum-enriched genes was measured in 6-hydroxydopamine-lesioned rats to determine their dependence on dopamine innervation. No changes in expression were observed for any of these genes. These findings demonstrate that mutant huntingtin protein causes selective deficits in the expression of mRNAs responsible for striatum-specific physiology and these may contribute to the regional specificity of degeneration observed in HD.