Lack of huntingtin-associated protein-1 causes neuronal death resembling hypothalamic degeneration in Huntington's disease.
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.
Li
Shi-Hua
SH
Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Yu
Zhao-Xue
ZX
Li
Cui-Lin
CL
Nguyen
Huu-Phuc
HP
Zhou
Yong-Xing
YX
Deng
Chuxia
C
Li
Xiao-Jiang
XJ
D000818:Animals; D001835:Body Weight / Q000235:genetics; D016923:Cell Death / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018450:Disease Progression; D066246:ErbB Receptors / Q000378:metabolism; D005247:Feeding Behavior; D005328:Fetal Viability / Q000235:genetics; D018390:Gene Targeting; D006720:Homozygote; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000473:pathology; D007031:Hypothalamus / Q000378:metabolism* / Q000473:pathology; D020287:In Situ Nick-End Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D011485:Protein Binding / Q000235:genetics; D051381:Rats; D015398:Signal Transduction
C490758:Hap1 protein, mouse; C490757:Hap1 protein, rat; C506812:Htt protein, mouse; C499524:Htt protein, rat; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D066246:ErbB Receptors