Li Shi-Hua, Yu Zhao-Xue, Li Cui-Lin, Nguyen Huu-Phuc, Zhou Yong-Xing, Deng Chuxia, Li Xiao-Jiang
Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
J Neurosci. 2003 Jul 30;23(17):6956-64. doi: 10.1523/JNEUROSCI.23-17-06956.2003.
Huntington's disease (HD) is caused by a polyglutamine expansion in the disease protein huntingtin. The polyglutamine expansion causes huntingtin to interact abnormally with a number of proteins. However, it is unclear whether, and how, huntingtin-associated proteins are involved in the neurodegeneration in HD. Here, we show that huntingtin-associated protein-1 (HAP1), which is involved in intracellular trafficking of epidermal growth factor receptor (EGFR), is highly expressed in the hypothalamus. Mice lacking HAP1 die after birth because of depressed feeding activity. Terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling staining and electron microscopic examination revealed the degeneration in hypothalamic regions that control feeding behavior. Hypothalamic degeneration was also observed in HD transgenic mice that have a significant loss of body weight. Inhibition of HAP1 expression decreases EGFR signaling and cell viability, whereas overexpression of HAP1 enhances this signaling activity and inhibits mutant huntingtin-mediated cytotoxicity. These results suggest that the effect of mutant huntingtin on HAP1 and EGFR signaling may contribute to the hypothalamic neurodegeneration and loss of body weight in HD.
亨廷顿舞蹈症（HD）由疾病蛋白亨廷顿蛋白中的多聚谷氨酰胺扩展所致。多聚谷氨酰胺扩展导致亨廷顿蛋白与多种蛋白质发生异常相互作用。然而，尚不清楚亨廷顿蛋白相关蛋白是否以及如何参与HD中的神经退行性变。在此，我们表明参与表皮生长因子受体（EGFR）细胞内运输的亨廷顿蛋白相关蛋白1（HAP1）在下丘脑中高度表达。缺乏HAP1的小鼠出生后因进食活动受抑制而死亡。末端脱氧核苷酸转移酶介导的生物素化UTP缺口末端标记染色和电子显微镜检查显示，控制进食行为的下丘脑区域发生了退化。在体重显著减轻的HD转基因小鼠中也观察到了下丘脑退化。抑制HAP1表达会降低EGFR信号传导和细胞活力，而HAP1的过表达则增强这种信号传导活性并抑制突变型亨廷顿蛋白介导的细胞毒性。这些结果表明，突变型亨廷顿蛋白对HAP1和EGFR信号传导的影响可能导致HD中的下丘脑神经退行性变和体重减轻。
