Increased huntingtin protein length reduces the number of polyglutamine-induced gene expression changes in mouse models of Huntington's disease
Increased huntingtin protein length reduces the number of polyglutamine-induced gene expression changes in mouse models of Huntington's disease
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DOI：
10.1093/hmg/11.17.1939
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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：
Chan, EYW;Luthi-Carter, R;Olson, JM
突变型亨廷顿蛋白（htt）的转录失调和蛋白水解被认为是亨廷顿病（HD）发病机制的重要组成部分。在之前的研究中，我们证明了表达含有171个或更少n端残基的短突变htt片段的转基因小鼠（R6/2和N171-82Q小鼠）再现了人类HD大脑中观察到的许多mRNA变化。为了研究htt蛋白长度是否影响其扩展的聚谷氨酰胺结构域改变基因表达的能力，我们对表达延长n端片段（HD46、HD100； 964个氨基酸）或全长突变型htt转蛋白的小鼠进行了mRNA谱分析。HD46和YAC72小鼠的寡核苷酸芯片分析发现，与表达短n端突变体htt片段的转基因小鼠相比，HD46和YAC72小鼠差异表达的mrna较少。组织学分析也发现这些小鼠的变化有限（HD100小鼠的腺苷A2a受体mRNA和多巴胺D2受体结合小幅度减少；HD46和HD100小鼠的多巴胺D1受体结合小幅度增加）。HD46和YAC72小鼠均未表现出与R6/2小鼠、N171-82Q小鼠或人类HD患者相似的mRNA水平改变。这些发现表明，htt蛋白长度影响扩展的聚谷氨酰胺结构域改变基因表达的能力。此外，我们的研究结果表明，突变体htt的短n端片段可能是人类HD大脑中观察到的基因表达改变的原因。
Both transcriptional dysregulation and proteolysis of mutant huntingtin (htt) are postulated to be important components of Huntington's disease (HD) pathogenesis. In previous studies, we demonstrated that transgenic mice that express short mutant htt fragments containing 171 or fewer N-terminal residues (R6/2 and N171-82Q mice) recapitulate many of the mRNA changes observed in human HD brain. To examine whether htt protein length influences the ability of its expanded polyglutamine domain to alter gene expression, we conducted mRNA profiling analyses of mice that express an extended N-terminal fragment (HD46, HD100; 964 amino acids) or full-length (YAC72; 3144 amino acids) mutant htt transprotein. Oligonucleotide microarray analyses of HD46 and YAC72 mice identified fewer differentially expressed mRNAs than were seen in transgenic mice expressing short N-terminal mutant htt fragments. Histologic analyses also detected limited changes in these mice (small decreases in adenosine A2a receptor mRNA and dopamine D2 receptor binding in HD100 animals; small increases in dopamine D1 receptor binding in HD46 and HD100 mice). Neither HD46 nor YAC72 mice exhibited altered mRNA levels similar to those observed previously in R6/2 mice, N171-82Q mice or human HD patients. These findings suggest that htt protein length influences the ability of an expanded polyglutamine domain to alter gene expression. Furthermore, our findings suggest that short N-terminal fragments of mutant htt might be responsible for the gene expression alterations observed in human HD brain.