Dysregulation of gene expression in the R6/2 model of polyglutamine disease: parallel changes in muscle and brain
Dysregulation of gene expression in the R6/2 model of polyglutamine disease: parallel changes in muscle and brain
复制标题
DOI：
10.1093/hmg/11.17.1911
复制
发表时间：
2002-08-15
影响因子：
3.5
通讯作者：
Olson, JM
中科院分区：
文献类型：
--
作者：
Luthi-Carter, R;Hanson, SA;Olson, JM
先前对亨廷顿氏病（R6/2）小鼠模型中基因表达的分析表明，突变亨廷顿蛋白的N-末端片段导致纹状体信号基因下调，特别是那些通常由cAMP和视黄酸诱导的基因。本研究通过评估受亨廷顿病和其他多聚谷氨酰胺疾病影响的其他大脑区域是否发生类似的变化，并通过辨别基因表达变化是否先于疾病体征的出现，扩大了先前工作的区域和时间范围。应用寡核苷酸芯片技术检测了症状性R6/2小鼠大脑皮质、小脑和纹状体中约11000个mRNA的表达。基因表达变化的数量和性质在这三个区域之间是相似的，正如预期的那样受到基线基因表达的区域差异的影响。时程研究表明，mRNA的变化只能在4周龄后可靠地检测到，与这些动物的早期病理和行为变化的发展相一致。此外，我们发现骨骼肌也是多聚谷氨酰胺相关的基因表达扰动的靶点，显示出在大脑和肌肉特异性mRNA中失调的mRNA的变化。完整的数据集可在www.neumetrix.info上查阅。
Previous analyses of gene expression in a mouse model of Huntington's disease (R6/2) indicated that an N-terminal fragment of mutant huntingtin causes downregulation of striatal signaling genes and particularly those normally induced by cAMP and retinoic acid. The present study expands the regional and temporal scope of this previous work by assessing whether similar changes occur in other brain regions affected in Huntington's disease and other polyglutamine diseases and by discerning whether gene expression changes precede the appearance of disease signs. Oligonucleotide microarrays were employed to survey the expression of similar to11 000 mRNAs in the cerebral cortex, cerebellum and striatum of symptomatic R6/2 mice. The number and nature of gene expression changes were similar among these three regions, influenced as expected by regional differences in baseline gene expression. Time-course studies revealed that mRNA changes could only reliably be detected after 4 weeks of age, coincident with development of early pathologic and behavioral changes in these animals. In addition, we discovered that skeletal muscle is also a target of polyglutamine-related perturbations in gene expression, showing changes in mRNAs that are dysregulated in brain and also muscle-specific mRNAs. The complete dataset is available at www.neumetrix.info.