Decreased expression of hypothalamic neuropeptides in Huntington disease transgenic mice with expanded polyglutamine-EGFP fluorescent aggregates
Decreased expression of hypothalamic neuropeptides in Huntington disease transgenic mice with expanded polyglutamine-EGFP fluorescent aggregates
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DOI：
10.1111/j.1471-4159.2005.03035.x
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发表时间：
2005-05-01
影响因子：
4.7
通讯作者：
Nukina, N
中科院分区：
文献类型：
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作者：
Kotliarova, S;Jana, NR;Nukina, N
亨廷顿病是由亨廷顿蛋白中的聚谷氨酰胺（polyQ）扩增引起的。在亨廷顿病的纹状体和大脑皮层中观察到选择性和进行性神经元丢失。我们已经讨论了扩大的多q聚集是否出现在大脑纹状体和皮层以外的区域，以及扩大的多q聚集形成与转录失调之间是否存在相关性。我们建立了表达突变型截断n端亨廷顿蛋白（扩增polyQ）与增强绿色荧光蛋白（EGFP）融合的转基因小鼠系，并利用从大脑中提取的mRNA进行高密度寡核苷酸阵列分析，随后进行TaqMan RT-PCR和原位杂交。转基因小鼠形成扩大的polyQ- egfp荧光聚集体，该系统使我们能够直接看到大脑各区域扩大的polyQ聚集体，而无需进行免疫组织化学研究。我们在这里发现，polyQ-EGFP聚集在下丘脑强烈，其中六种下丘脑神经肽mrna的表达，如催产素，抗利尿激素和可卡因-安非他明调节转录物，在转基因小鼠大脑中被下调，而没有观察到下丘脑神经元的显著损失。这些结果表明，这些小鼠的下丘脑容易形成聚集体，这可能导致大脑该区域特定基因的下调。
Huntington disease is caused by polyglutamine (polyQ) expansion in huntingtin. Selective and progressive neuronal loss is observed in the striatum and cerebral cortex in Huntington disease. We have addressed whether expanded polyQ aggregates appear in regions of the brain apart from the striatum and cortex and whether there is a correlation between expanded polyQ aggregate formation and dysregulated transcription. We generated transgenic mouse lines expressing mutant truncated N-terminal huntingtin (expanded polyQ) fused with enhanced green fluorescent protein (EGFP) and carried out a high-density oligonucleotide array analysis using mRNA extracted from the cerebrum, followed by TaqMan RT-PCR and in situ hybridization. The transgenic mice formed expanded polyQ-EGFP fluorescent aggregates and this system allowed us to directly visualize expanded polyQ aggregates in various regions of the brain without performing immunohistochemical studies. We show here that polyQ-EGFP aggregates were intense in the hypothalamus, where the expression of six hypothalamic neuropeptide mRNAs, such as oxytocin, vasopressin and cocaine-amphetamine-regulated transcript, was down-regulated in the transgenic mouse brain without observing a significant loss of hypothalamic neurons. These results indicate that the hypothalamus is susceptible to aggregate formation in these mice and this may result in the down-regulation of specific genes in this region of the brain.