Neuronal function of huntingtin associated protein Huntingtin-associated protein-1 (Hap1) was first identified as a cytoplasmic protein that interacts with the Huntington disease protein huntingtin. Like huntingtin, which is critical for embryonic development, Hap1 is also essential for animal survival, as deletion of the Hap1 gene in the mouse leads to a retarded growth and early postnatal death. However, unlike huntingtin, which is ubiquitously expressed, Hap1 is enriched in the brain and is expressed at different levels in various types of neurons, suggesting that Hap1 may function differently in different brain regions. Our recent studies also show that Hap1 forms a stable complex with Ahi1, a protein whose mutations cause Joubert syndrome, which is a brain developmental disorder. Growing evidence has demonstrated that Hap1 associates with microtubule-dependent transporters and that both huntingtin and Hap1 participate in intracellular trafficking. More importantly, mutant huntingtin can affect Hap1-mediated transport of vesicles and membrane receptors. While these findings have proved our previous hypothesis that Hap1 is involved in intracellular trafficking, the mechanism underlying the trafficking function of Hap1 remains to be investigated. Understanding this mechanism is important for unraveling the complex regulation of intracellular transport of membrane receptors and the neuropathology related to impaired intracellular trafficking. We hypothesize that Hap1 dysfunction may cause neuropathology in an age- and/or brain regional dependent manner and that phosphorylation of Hap1 regulates its function in endocytosis of membrane receptors.
In Aim 1, we will utilize the conditional Hap1 knockout mice to selectively deplete Hap1 expression in different brain regions and at different ages. We will then examine the neuropathology and behavioral phenotypes of Hap1 mutant mice to determine the critical function of Hap1.
In Aim 2, we will investigate how Hap1 participates in the endocytosis and recycling of neurotrophic receptors and whether mutant huntingtin affects Hap1-associated endocytosis of Trk receptors in an age-dependent manner. The studies aim to provide mechanistic insight into intracellular trafficking and endocytosis of membrane receptors and also offer a therapeutic target for the neuropathology caused by impaired endocytosis of neurotrophic receptors.

Public Health Relevance

Characterization of the neuronal function of huntingtin associated protein (HAP1) will lead to increased understanding of the mechanisms for intracellular trafficking and pathogenesis of neuropathological conditions related to the impaired intracellular trafficking. ! !

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS036232-13
Application #
8238661
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Sutherland, Margaret L
Project Start
1998-01-01
Project End
2016-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
13
Fiscal Year
2012
Total Cost
$335,453
Indirect Cost
$116,703
Name
Emory University
Department
Genetics
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Wang, Guohao; Liu, Xudong; Gaertig, Marta A et al. (2016) Ablation of huntingtin in adult neurons is nondeleterious but its depletion in young mice causes acute pancreatitis. Proc Natl Acad Sci U S A 113:3359-64
Yin, Peng; Tu, Zhuchi; Yin, An et al. (2015) Aged monkey brains reveal the role of ubiquitin-conjugating enzyme UBE2N in the synaptosomal accumulation of mutant huntingtin. Hum Mol Genet 24:1350-62
Niu, Yuyu; Guo, Xiangyu; Chen, Yongchang et al. (2015) Early Parkinson's disease symptoms in α-synuclein transgenic monkeys. Hum Mol Genet 24:2308-17
Huang, Shanshan; Yang, Su; Guo, Jifeng et al. (2015) Large Polyglutamine Repeats Cause Muscle Degeneration in SCA17 Mice. Cell Rep 13:196-208
Jiang, Wenxiao; Wei, Wenjie; Gaertig, Marta A et al. (2015) Therapeutic Effect of Berberine on Huntington's Disease Transgenic Mouse Model. PLoS One 10:e0134142
Yang, Weili; Wang, Guohao; Wang, Chuan-En et al. (2015) Mutant alpha-synuclein causes age-dependent neuropathology in monkey brain. J Neurosci 35:8345-58
Huang, Brenda; Wei, WenJie; Wang, Guohao et al. (2015) Mutant huntingtin downregulates myelin regulatory factor-mediated myelin gene expression and affects mature oligodendrocytes. Neuron 85:1212-26
Xiang, Jianxing; Yan, Sen; Li, Shi-Hua et al. (2015) Postnatal loss of hap1 reduces hippocampal neurogenesis and causes adult depressive-like behavior in mice. PLoS Genet 11:e1005175
Tu, Zhuchi; Yang, Weili; Yan, Sen et al. (2015) CRISPR/Cas9: a powerful genetic engineering tool for establishing large animal models of neurodegenerative diseases. Mol Neurodegener 10:35
Chen, Yongchang; Zheng, Yinghui; Kang, Yu et al. (2015) Functional disruption of the dystrophin gene in rhesus monkey using CRISPR/Cas9. Hum Mol Genet 24:3764-74

Showing the most recent 10 out of 57 publications