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The Journal of Neuroscience, July 30, 2003, 23(17):6956-6964

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 Previous Article

Lack of Huntingtin-Associated Protein-1 Causes Neuronal Death Resembling Hypothalamic Degeneration in Huntington's Disease

Shi-Hua Li,1 Zhao-Xue Yu,1 Cui-Lin Li,2 Huu-Phuc Nguyen,1 Yong-Xing Zhou,2 Chuxia Deng,2 and Xiao-Jiang Li1

1Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322, and 2Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892

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.

Key words: hypothalamus; degeneration; EGFR; Huntington; polyglutamine; huntingtin

Received Mar. 24, 2003; revised May. 29, 2003; accepted Jun. 4, 2003.




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