Kotliarova Svetlana, Jana Nihar R, Sakamoto Naoaki, Kurosawa Masaru, Miyazaki Haruko, Nekooki Munenori, Doi Hiroshi, Machida Yoko, Wong Hon Kit, Suzuki Taishi, Uchikawa Chiharu, Kotliarov Yuri, Uchida Kazuyo, Nagao Yoshiro, Nagaoka Utako, Tamaoka Akira, Oyanagi Kiyomitsu, Oyama Fumitaka, Nukina Nobuyuki
Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan.
J Neurochem. 2005 May;93(3):641-53. doi: 10.1111/j.1471-4159.2005.03035.x.
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.
亨廷顿舞蹈症是由亨廷顿蛋白中的多聚谷氨酰胺（polyQ）扩增引起的。在亨廷顿舞蹈症患者的纹状体和大脑皮层中可观察到选择性和进行性的神经元丧失。我们研究了除纹状体和皮层外，多聚谷氨酰胺扩增聚集体是否出现在大脑的其他区域，以及多聚谷氨酰胺扩增聚集体的形成与转录失调之间是否存在关联。我们构建了表达与增强型绿色荧光蛋白（EGFP）融合的突变型截短N端亨廷顿蛋白（多聚谷氨酰胺扩增）的转基因小鼠品系，并使用从大脑提取的mRNA进行了高密度寡核苷酸阵列分析，随后进行了TaqMan RT-PCR和原位杂交。转基因小鼠形成了多聚谷氨酰胺-EGFP荧光聚集体，该系统使我们无需进行免疫组织化学研究就能直接观察到大脑各个区域的多聚谷氨酰胺扩增聚集体。我们在此表明，多聚谷氨酰胺-EGFP聚集体在下丘脑中强烈表达，在转基因小鼠大脑中，催产素、加压素和可卡因-安非他明调节转录物等六种下丘脑神经肽mRNA的表达下调，而下丘脑神经元未出现明显丧失。这些结果表明，下丘脑在这些小鼠中易形成聚集体，这可能导致该脑区特定基因的下调。
