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