-
Ling Weng,
Yung-Feng Lin,
Alina L Li,
Chuan-En Wang,
Sen Yan,
Miao Sun,
Marta A Gaertig,
Naureen Mitha,
Jun Kosaka,
Taketoshi Wakabayashi,
Xingshun Xu,
Beisha Tang,
Shihua Li, Xiao-Jiang Li
[show abstract]
[hide abstract]
ABSTRACT: Mutations in the Abelson helper integration site-1 (AHI1) gene result in N-terminal Ahi1 fragments and cause Joubert syndrome, an autosomal recessive brain malformation disorder associated with delayed development. How AHI1 mutations lead to delayed development remains unclear. Here we report that full-length, but not N-terminal, Ahi1 binds Hap1, a huntingtin-associated protein that is essential for the postnatal survival of mice and that this binding is regulated during neuronal differentiation by nerve growth factor. Nerve growth factor induces dephosphorylation of Hap1A and decreases its association with Ahi1, correlating with increased Hap1A distribution in neurite tips. Consistently, Ahi1 associates with phosphorylated Hap1A in cytosolic, but not in synaptosomal, fractions isolated from mouse brain, suggesting that Ahi1 functions mainly in the soma of neurons. Mass spectrometry analysis of cytosolic Ahi1 immunoprecipitates reveals that Ahi1 also binds Cend1 (cell cycle exit and neuronal differentiation protein 1)/BM88, a neuronal protein that mediates neuronal differentiation and is highly expressed in postnatal mouse brain. Loss of Ahi1 reduces the levels of Cend1 in the hypothalamus of Ahi1 KO mice, which show retarded growth during postnatal days. Overexpressed Ahi1 can stabilize Cend1 in cultured cells. Furthermore, overexpression of Cend1 can rescue the neurite extension defects of hypothalamic neurons from Ahi1 KO mice. Our findings suggest that Cend1 is involved in Ahi1-associated hypothalamic neuronal differentiation in early development, giving us fresh insight into the mechanism behind the delayed development in Joubert syndrome.
Journal of Neuroscience 05/2013; 33(19):8172-8184. · 7.11 Impact Factor
-
Journal of Genetics and Genomics 06/2012; 39(6):237-8. · 1.88 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Transgenic animal models have revealed much about the pathogenesis of age-dependent neurodegenerative diseases and proved to be a useful tool for uncovering therapeutic targets. Huntington's disease is a well-characterized neurodegenerative disorder that is caused by expansion of a CAG repeat, which results in expansion of a polyglutamine tract in the N-terminal region of huntingtin (HTT). Similar CAG/glutamine expansions are also found to cause eight other neurodegenerative diseases that affect distinct brain regions in an age-dependent manner. Identification of this CAG/glutamine expansion has led to the generation of a variety of transgenic animal models. Of these different animal models, transgenic mice have been investigated extensively, and they show similar neuropathology and phenotypes as seen in their respective diseases. The common pathological hallmark of age-dependent neurodegeneration is the formation of aggregates or inclusions consisting of misfolded proteins in the affected brain regions; however, overt or striking neurodegeneration and apoptosis have not been reported in most transgenic mouse models for age-dependent diseases, including HD. By comparing the neuropathology of transgenic HD mouse, pig, and monkey models, we found that mutant HTT is more toxic to larger animals than mice, and larger animals also show neuropathology that has not been uncovered by transgenic mouse models. This review will discuss the importance of transgenic large animal models for analyzing the pathogenesis of neurodegenerative diseases and developing effective treatments.
Journal of Genetics and Genomics 06/2012; 39(6):239-45. · 1.88 Impact Factor
-
Austin Cape,
Xingxing Chen,
Chuan-En Wang,
Ashley O’Neill,
Yung-Feng Lin,
Jun He,
Xing-Shun Xu,
Hong Yi,
He Li,
Shihua Li, Xiao-Jiang Li
[show abstract]
[hide abstract]
ABSTRACT: Hap1 was originally identified as a neuronal protein that interacts with huntingtin, the Huntington’s disease (HD) protein.
Later studies revealed that Hap1 participates in intracellular trafficking in neuronal cells and that this trafficking function
can be adversely affected by mutant huntingtin. Hap1 is also present in pancreatic β-cells and other endocrine cells; however,
the role of Hap1 in these endocrine cells remains unknown. Using the Cre-loxP system, we generated conditional Hap1 knockout
mice to selectively deplete the expression of Hap1 in mouse pancreatic β-cells. Mutant mice with Hap1 deficiency in pancreatic
β-cells had impaired glucose tolerance and decreased insulin release in response to intraperitoneally injected glucose. Using
cultured pancreatic β-cell lines and isolated mouse pancreatic islets, we confirmed that decreasing Hap1 could reduce glucose-mediated
insulin release. Electron microscopy suggested that there was a reduced number of insulin-containing vesicles docked at the
plasma membrane of pancreatic islets in Hap1 mutant mice following intraperitoneal glucose injection. Glucose treatment decreased
the phosphorylation of Hap1A in cultured β-cells and in mouse pancreatic tissues. Moreover, this glucose treatment increased
Hap1’s association with kinesin light chain and dynactin p150, both of which are involved in microtubule-dependent trafficking.
These studies suggest that Hap1 is important for insulin release from β-cells via dephosphorylation that can regulate its
intracellular trafficking function.
KeywordsHuntingtin–Trafficking–Insulin–Pancreas–Phosphorylation
Cellular and Molecular Life Sciences CMLS 04/2012; 69(8):1305-1317. · 6.57 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Huntington's disease (HD) is caused by expansion of a polyglutamine repeat in the N-terminal region of huntingtin (htt), a large protein that has been found to interact with a variety of proteins. It remains to be determined how the interactions of htt with other proteins are involved in the pathogenesis of HD. A recent publication by Keryer et al. demonstrates that htt regulates ciliogenesis by interacting with PCM1 through HAP1. This recent study shows that htt and HAP1 are essential for protein trafficking to the centrosome, as well as normal ciliogenesis, and that mutant htt causes abnormal ciliogenesis, providing a novel insight into the pathogenesis of HD.
Expert Review of Proteomics 01/2012; 9(1):17-9. · 3.68 Impact Factor
-
Hao Wang,
Zhenbo Huang,
Liansha Huang,
Shaona Niu,
Xiurong Rao,
Jing Xu,
Hui Kong,
Jianzhong Yang,
Chuan Yang,
Donghai Wu,
Shihua Li, Xiao-Jiang Li,
Tonghua Liu,
Guoqing Sheng
[show abstract]
[hide abstract]
ABSTRACT: It is indicated that there are important molecules interacting with brain nervous systems to regulate feeding and energy balance by influencing the signaling pathways of these systems, but relatively few of the critical players have been identified. In the present study, we provide the evidence for the role of Abelson helper integration site 1 (Ahi1) protein as a mediator of feeding behavior through interaction with serotonin receptor 2C (5-HT(2C)R), known for its critical role in feeding and appetite control. First, we demonstrated the co-localization and interaction between hypothalamic Ahi1 and 5-HT(2C)R. Ahi1 promoted the degradation of 5-HT(2C)R through the lysosomal pathway. Then, we investigated the effects of fasting on the expression of hypothalamic Ahi1 and 5-HT(2C)R. Fasting resulted in an increased Ahi1 expression and a concomitant decreased expression of 5-HT(2C)R. Knockdown of hypothalamic Ahi1 led to a concomitant increased expression of 5-HT(2C)R and a decrease of food intake and body weight. Last, we found that Ahi1 could regulate the expression of neuropeptide Y and proopiomelanocortin. Taken together, our results indicate that Ahi1 mediates feeding behavior by interacting with 5-HT(2C)R to modulate the serotonin signaling pathway.
Journal of Biological Chemistry 11/2011; 287(3):2237-46. · 4.77 Impact Factor
-
Madhuchhanda Mandal,
Jing Wei,
Ping Zhong,
Jia Cheng,
Lara J. Duffney,
Wenhua Liu,
Eunice Y. Yuen,
Alison E. Twelvetrees,
Shihua Li, Xiao-Jiang Li,
Josef T. Kittler,
Zhen Yan
[show abstract]
[hide abstract]
ABSTRACT: Emerging evidence from studies of Huntington disease (HD) pathophysiology suggests that huntingtin (htt) and its associated
protein HAP1 participate in intracellular trafficking and synaptic function. However, it is largely unknown whether AMPA receptor
trafficking, which is crucial for controlling the efficacy of synaptic excitation, is affected by the mutant huntingtin with
polyglutamine expansion (polyQ-htt). In this study, we found that expressing polyQ-htt in neuronal cultures significantly
decreased the amplitude and frequency of AMPAR-mediated miniature excitatory postsynaptic current (mEPSC), while expressing
wild-type huntingtin (WT-htt) increased mEPSC. AMPAR-mediated synaptic transmission was also impaired in a transgenic mouse
model of HD expressing polyQ-htt. The effect of polyQ-htt on mEPSC was mimicked by knockdown of HAP1 and occluded by the dominant
negative HAP1. Moreover, we found that huntingtin affected mESPC via a mechanism depending on the kinesin motor protein, KIF5,
which controls the transport of GluR2-containing AMPARs along microtubules in dendrites. The GluR2/KIF5/HAP1 complex was disrupted
and dissociated from microtubules in the HD mouse model. Together, these data suggest that AMPAR trafficking and function
is impaired by mutant huntingtin, presumably due to the interference of KIF5-mediated microtubule-based transport of AMPA
receptors. The diminished strength of glutamatergic transmission could contribute to the deficits in movement control and
cognitive processes in HD conditions.
Journal of Biological Chemistry 09/2011; 286(39):33719-33728. · 4.77 Impact Factor
-
Madhuchhanda Mandal,
Jing Wei,
Ping Zhong,
Jia Cheng,
Lara J Duffney,
Wenhua Liu,
Eunice Y Yuen,
Alison E Twelvetrees,
Shihua Li, Xiao-Jiang Li,
Josef T Kittler,
Zhen Yan
[show abstract]
[hide abstract]
ABSTRACT: Emerging evidence from studies of Huntington disease (HD) pathophysiology suggests that huntingtin (htt) and its associated protein HAP1 participate in intracellular trafficking and synaptic function. However, it is largely unknown whether AMPA receptor trafficking, which is crucial for controlling the efficacy of synaptic excitation, is affected by the mutant huntingtin with polyglutamine expansion (polyQ-htt). In this study, we found that expressing polyQ-htt in neuronal cultures significantly decreased the amplitude and frequency of AMPAR-mediated miniature excitatory postsynaptic current (mEPSC), while expressing wild-type huntingtin (WT-htt) increased mEPSC. AMPAR-mediated synaptic transmission was also impaired in a transgenic mouse model of HD expressing polyQ-htt. The effect of polyQ-htt on mEPSC was mimicked by knockdown of HAP1 and occluded by the dominant negative HAP1. Moreover, we found that huntingtin affected mESPC via a mechanism depending on the kinesin motor protein, KIF5, which controls the transport of GluR2-containing AMPARs along microtubules in dendrites. The GluR2/KIF5/HAP1 complex was disrupted and dissociated from microtubules in the HD mouse model. Together, these data suggest that AMPAR trafficking and function is impaired by mutant huntingtin, presumably due to the interference of KIF5-mediated microtubule-based transport of AMPA receptors. The diminished strength of glutamatergic transmission could contribute to the deficits in movement control and cognitive processes in HD conditions.
Journal of Biological Chemistry 08/2011; 286(39):33719-28. · 4.77 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The polyglutamine diseases consist of nine neurodegenerative disorders including spinocerebellar ataxia type 17 that is caused by a polyglutamine tract expansion in the TATA box-binding protein. In all polyglutamine diseases, polyglutamine-expanded proteins are ubiquitously expressed throughout the body but cause selective neurodegeneration. Understanding the specific effects of polyglutamine-expanded proteins, when expressed at the endogenous levels, in neurons is important for unravelling the pathogenesis of polyglutamine diseases. However, addressing this important issue using mouse models that either overly or ubiquitously express mutant polyglutamine proteins in the brain and body has proved difficult. To investigate the pathogenesis of spinocerebellar ataxia 17, we generated a conditional knock-in mouse model that expresses one copy of the mutant TATA box-binding protein gene, which encodes a 105-glutamine repeat, selectively in neuronal cells at the endogenous level. Neuronal expression of mutant TATA box-binding protein causes age-dependent neurological symptoms in mice and the degeneration of cerebellar Purkinje cells. Mutant TATA box-binding protein binds more tightly to the transcription factor nuclear factor-Y, inhibits its association with the chaperone protein promoter, as well as the promoter activity and reduces the expression of the chaperones Hsp70, Hsp25 and HspA5, and their response to stress. These findings demonstrate how mutant TATA box-binding protein at the endogenous level affects neuronal function, with important implications for the pathogenesis and treatment of polyglutamine diseases.
Brain 07/2011; 134(Pt 7):1943-58. · 9.46 Impact Factor
-
Austin Cape,
Xingxing Chen,
Chuan-En Wang,
Ashley O'Neill,
Yung-Feng Lin,
Jun He,
Xing-Shun Xu,
Hong Yi,
He Li,
Shihua Li, Xiao-Jiang Li
[show abstract]
[hide abstract]
ABSTRACT: Hap1 was originally identified as a neuronal protein that interacts with huntingtin, the Huntington's disease (HD) protein. Later studies revealed that Hap1 participates in intracellular trafficking in neuronal cells and that this trafficking function can be adversely affected by mutant huntingtin. Hap1 is also present in pancreatic β-cells and other endocrine cells; however, the role of Hap1 in these endocrine cells remains unknown. Using the Cre-loxP system, we generated conditional Hap1 knockout mice to selectively deplete the expression of Hap1 in mouse pancreatic β-cells. Mutant mice with Hap1 deficiency in pancreatic β-cells had impaired glucose tolerance and decreased insulin release in response to intraperitoneally injected glucose. Using cultured pancreatic β-cell lines and isolated mouse pancreatic islets, we confirmed that decreasing Hap1 could reduce glucose-mediated insulin release. Electron microscopy suggested that there was a reduced number of insulin-containing vesicles docked at the plasma membrane of pancreatic islets in Hap1 mutant mice following intraperitoneal glucose injection. Glucose treatment decreased the phosphorylation of Hap1A in cultured β-cells and in mouse pancreatic tissues. Moreover, this glucose treatment increased Hap1's association with kinesin light chain and dynactin p150, both of which are involved in microtubule-dependent trafficking. These studies suggest that Hap1 is important for insulin release from β-cells via dephosphorylation that can regulate its intracellular trafficking function.
Cellular and Molecular Life Sciences CMLS 05/2011; 69(8):1305-17. · 6.57 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: An expanded polyglutamine tract (>37 glutamines) in the N-terminal region of huntingtin (htt) causes htt to accumulate in the nucleus, leading to transcriptional dysregulation in Huntington disease (HD). In HD knock-in mice that express full-length mutant htt at the endogenous level, mutant htt preferentially accumulates in the nuclei of striatal neurons, which are affected most profoundly in HD. The mechanism underlying this preferential nuclear accumulation of mutant htt in striatal neurons remains unknown. Here, we report that serine 16 (S16) in htt is important for the generation of small N-terminal fragments that are able to accumulate in the nucleus and form aggregates. Phosphorylation of N-terminal S16 in htt promotes the nuclear accumulation of small N-terminal fragments and reduces the interaction of N-terminal htt with the nuclear pore complex protein Tpr. Mouse brain striatal tissues show increased S16 phosphorylation and a decreased association between mutant N-terminal htt and Tpr. These findings provide mechanistic insight into the nuclear accumulation of mutant htt and the selective neuropathology of HD, revealing potential therapeutic targets for treating this disease.
Human Molecular Genetics 02/2011; 20(7):1424-37. · 7.64 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The function of the brainstem Hap1-Ahi1 complex in the regulation of feeding behavior was investigated. When mice were fasted or treated with 2-deoxy-D-glucose (2-DG), Hap1-Ahi1 was significantly upregulated. By using streptozotocin (STZ) to decrease the circulating insulin in mice, Hap1-Ahi1 was significantly increased. Furthermore, intra-brain injection of insulin decreased the expression of Hap1-Ahi1 in the brainstem. Moreover, when we knocked down the expression of brainstem Hap1 by RNAi, the mice showed decreased food intake and lower body weights. Collectively, our results indicate that the Hap1-Ahi1 complex in the brainstem works as a sensor for insulin signals in feeding control.
FEBS letters 01/2011; 585(1):85-91. · 3.54 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The ubiquitin–proteasome system (UPS) is responsible for clearing most soluble proteins in the cytoplasm and nucleus. Recent
studies reveal that the UPS function is critical for maintaining synaptic plasticity and transmission and that the UPS dysfunction
is associated with axonal degeneration and impaired synaptic transmission. In this chapter, we will focus on the role of the
UPS in synapses and the association of UPS impairment with neurological disorders. Since protein misfolding causes several
neurological disorders that show synaptic dysfunction during the early stages of disease, understanding the involvement of
the synaptic UPS in neurological disorders may help determine effective strategies for treating neurological disorders caused
by the accumulation of misfolded proteins.
12/2010: pages 201-212;
-
[show abstract]
[hide abstract]
ABSTRACT: Protein degradation plays a central role in many cellular functions. Misfolded and damaged proteins are removed from the cells to avoid toxicity. Eukaryotic cells have two main routes for clearing misfolded or toxic proteins: the ubiquitin-proteasome and autophagy-lysosome pathways. The ubiquitin-proteasome system (UPS) is ubiquitously present in the cytoplasm, nucleus, and various subcellular regions whereas autophagy predominantly functions in the cytoplasm. The activity of the UPS often remains at a high level, whereas basal autophagy constitutively occurs at low levels in cells for the performance of homeostatic functions. Because of the presence of the UPS in the nucleus, the UPS function may be more important for clearing misfolded proteins in the nucleus. Polyglutamine diseases, including Huntington disease (HD), show the age-dependent neurological symptoms and the accumulation of misfolded proteins that are often found in the nucleus. The selective neuropathology in HD is also found to associate with the preferential accumulation of the disease protein huntingtin in neuronal cells. Although it is clear that the UPS is important for clearing mutant huntingtin, it remains unclear whether aging or HD affects the capacity of neuronal UPS to remove toxic and misfolded proteins. In this review, we focus on the relationship between the UPS function and aging as well as Huntington disease. We also discuss findings that suggest that aging is a more important factor that can negatively impact the function of the UPS. This article is part of a Special Issue entitled "Autophagy and protein degradation in neurological diseases."
Neurobiology of Disease 12/2010; 43(1):4-8. · 5.40 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Huntington's disease results from expansion of a glutamine repeat (>36 glutamines) in the N-terminal region of huntingtin (htt) and is characterized by preferential neurodegeneration in the striatum of the brain. N171-82Q mice that express N-terminal 171 amino acids of htt with an 82-glutamine repeat show severe neurological phenotypes and die early, suggesting that N-terminal mutant htt is pathogenic. In addition, various cellular factors and genetic modifiers are found to modulate the cytotoxicity of mutant htt. Understanding the contribution of these factors to HD pathogenesis will help identify therapeutics for this disease. To investigate the role of interleukin type 1 (IL-1), a cytokine that has been implicated in various neurological diseases, in HD neurological symptoms, we crossed N171-82Q mice to type I IL-1 receptor (IL-1RI) knockout mice. Mice lacking IL-1RI and expressing N171-82Q show more severe neurological symptoms than N171-82Q or IL-1RI knockout mice, suggesting that lack of IL-1RI can promote the neuronal toxicity of mutant htt. Lack of IL-1RI also increases the accumulation of transgenic mutant htt in the striatum in N171-82Q mice. Since IL-1RI signaling mediates both toxic and protective effects on neurons, its basal function and protective effects may be important for preventing the neuropathology seen in HD.
Molecular Brain 11/2010; 3:33.
-
Dongshan Yang,
Chuan-En Wang,
Bentian Zhao,
Wei Li,
Zhen Ouyang,
Zhaoming Liu,
Huaqiang Yang,
Pei Fan,
Ashley O'Neill,
Weiwang Gu,
Hong Yi,
Shihua Li,
Liangxue Lai, Xiao-Jiang Li
[show abstract]
[hide abstract]
ABSTRACT: Neurodegeneration is a hallmark of many neurological diseases, including Alzheimer's, Parkinson's and the polyglutamine diseases, which are all caused by misfolded proteins that accumulate in neuronal cells of the brain. Although apoptosis is believed to contribute to neurodegeneration in these cases, genetic mouse models of these diseases often fail to replicate apoptosis and overt neurodegeneration in the brain. Using nuclear transfer, we generated transgenic Huntington's disease (HD) pigs that express N-terminal (208 amino acids) mutant huntingtin with an expanded polyglutamine tract (105Q). Postnatal death, dyskinesia and chorea-like movement were observed in some transgenic pigs that express mutant huntingtin. Importantly, the transgenic HD pigs, unlike mice expressing the same transgene, displayed typical apoptotic neurons with DNA fragmentation in their brains. Also, expression of mutant huntingtin resulted in more neurons with activated caspase-3 in transgenic pig brains than that in transgenic mouse brains. Our findings suggest that species differences determine neuropathology and underscore the importance of large mammalian animals for modeling neurological disorders.
Human Molecular Genetics 10/2010; 19(20):3983-94. · 7.64 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Recent studies suggest that the human Abelson helper integration site-1 (AHI1) gene on chromosome 6 is associated with susceptibility to schizophrenia and autism, two common neuropsychological disorders with depression symptoms. Mouse Ahi1 protein is abundant in the hypothalamus and amygdala, which are important brain regions for controlling emotion. However, the neuronal function of Ahi1 remains unclear. With the Cre-loxP system, we created a mouse model that selectively reduces Ahi1 expression in neuronal cells. Mice with neuronal Ahi1 deficiency show reduced TrkB level in the brain and depressive phenotypes, which can be alleviated by antidepressant drugs or by overexpression of TrkB in the amygdala. Ahi1 deficiency promotes the degradation of endocytic TrkB and reduces TrkB signaling in neuronal cells. Our findings suggest that impaired endocytic sorting and increased degradation of TrkB can induce depression and that this impaired pathway may serve as a previously uncharacterized therapeutic target for depression.
Proceedings of the National Academy of Sciences 10/2010; 107(44):19126-31. · 9.68 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Mutant huntingtin (htt) carries an expanded polyglutamine (polyQ) repeat (> 36 glutamines) in its N-terminal region, which leads htt to become misfolded and kill neuronal cells in Huntington disease (HD). The cytotoxicity of N-terminal mutant htt fragments is evident by severe neurological phenotypes of transgenic mice that express these htt fragments. Clearance of mutant htt is primarily mediated by the ubiquitin-proteasomal sysmtem (UPS) and autophagy. However, the relative efficiency of these two systems to remove toxic forms of mutant htt has not been rigorously compared. Using cellular and mouse models of HD, we found that inhibiting the UPS leads to a greater accumulation of mutant htt than inhibiting autophagy. Moreover, N-terminal mutant htt fragments, but not full-length mutant htt, accumulate in the HD mouse brains after inhibiting the UPS. These findings suggest that the UPS is more efficient than autophagy to remove N-terminal mutant htt.
Autophagy 07/2010; 6(5). · 7.45 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The neurodegenerative polyglutamine diseases are caused by an expansion of unstable polyglutamine repeats in various disease proteins. Although these mutant proteins are expressed ubiquitously in neuronal and non-neuronal cells, they cause selective degeneration of specific neuronal populations. Recently, increasing evidence shows that polyglutamine disease proteins also affect non-neuronal cells. However, it remains unclear how the expression of polyglutamine proteins in non-neuronal cells contributes to the course of the polyglutamine diseases. Here, we discuss recent findings about the expression of mutant polyglutamine proteins in non-neuronal cells and their influence on neurological symptoms. Understanding the contribution of non-neuronal polyglutamine proteins to disease progression will help elucidate disease mechanisms and also help in the development of new treatment options.
Cell Research 03/2010; 20(4):400-7. · 8.19 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Huntingtin-associated protein-1 (Hap1) is a neuronal protein that associates with huntingtin, the Huntington disease protein. Although Hap1 and huntingtin are known to be involved in intracellular trafficking, whether and how the impairment of Hap1-associated trafficking leads to neurological pathology and symptoms remain to be seen. As Hap1 is enriched in neuronal cells in the brain, addressing this issue is important in defining the role of defective intracellular trafficking in the selective neuropathology associated with Hap1 dysfunction. Here, we find that Hap1 is abundantly expressed in orexin (hypocretin)-producing neurons (orexin neurons), which are distinctly distributed in the hypothalamus and play an important role in the regulation of feeding and behavior. We created conditional Hap1 knock-out mice to selectively deplete Hap1 in orexin neurons via the Cre-loxP system. These mice show process fragmentation of orexin neurons and reductions in food intake, body weight, and locomotor activity. Sucrose density gradient fractionation reveals that loss of Hap1 in the mouse brain also reduces the distribution of trafficking protein complexes and cargo proteins in the fractions that are enriched in synaptosomes. These results suggest that Hap1 is critical for the transport of multiple proteins to the nerve terminals to maintain the integrity of neuronal processes and that selective disruption of the processes of orexin neurons can cause abnormal feeding and locomotor activity.
Journal of Biological Chemistry 03/2010; 285(21):15941-9. · 4.77 Impact Factor
