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

Abstract

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.

DYRK1A regulates Hap1–Dcaf7/WDR68 binding with implication for delayed growth in Down syndrome

“…The highest P/S ratio of Hap1 was seen in the hypothalamus (Fig. 1B), in agreement with the finding that SBs are more abundant in the hypothalamus than in other tissues (5,10,14). Thus, these results showed that the use of a detergent-based strategy to enrich SBs in mouse brain was feasible.…”

“…DYRK1A is a major candidate gene for DS and likely is responsible for selective DS phenotypes. To look for DS symptoms that could be related to the regulation of DYRK1A on the Dcaf7-Hap1 interaction, we focused on growth retardation, which is a cardinal feature of DS (56) and is the most noticeable phenotype in Hap1-KO mice (5,10). Both individuals with DS and Hap1-KO mice exhibit impaired growth velocity after birth; the difference, however, is that in DS, growth velocity is most reduced between 6 mo and 3 y of age (56,57), whereas Hap1-KO mice are born at normal weight but display severe failure in body weight gain shortly after birth (5, 10).…”

“…or The Johns Hopkins University (M015M347) (R.H.R.). Generation of germline Hap1-KO mice and tamoxifen-inducible Cre-ER/floxedHap1 mice was described previously (5,11). Brain tissues of Ts65Dn mice were provided by R.H.R.…”

“…Hap1 was initially recognized for its binding to polyglutamine-expanded huntingtin (Htt), the protein responsible for Huntington's disease (3). Because Hap1 is expressed at various levels in different types of neurons (1,(4)(5)(6)(7)(8), it is likely involved in cell type-specific functions of the brain. For example, Hap1 is abundantly expressed in the hypothalamus, and its expression in the hypothalamus influences the central control of feeding (9); as a direct result, mice lacking Hap1 are malnourished and die in the early postnatal period (5, 10, 11).…”

Les astrocytes dans la chorée de Huntington

“…Ainsi, le nombre de sites de recapture du glutamate serait régulé chez la drosophile et les mammifères par la voie de signalisation du récepteur à l'EGF [23]. Des données in vitro sur des cellules PC12 en culture ont montré que la protéine Huntingtine mutée inhibe l'activation de ERK et AKT consécutive à la stimulation du récepteur à l'EGF [24,25]. Nous avons donc fait l'hypothèse que la présence de longues chaînes de résidus glutamine modifierait l'expression de gènes essentiels pour le fonctionnement du système nerveux en altérant, entre autres, la voie de signalisation du récepteur à l'EGF dans les cellules gliales.…”