Huntingtin associated protein-1 (HAP1) is enriched in neurons and is found to be involved in intracellular trafficking. The role of HAP1 in intracellular trafficking is supported by its interactions with a number of proteins including dynactin p150 and kinesin, which are involved in microtubule-dependent transport. Recent studies also suggest that HAP1 participates in vesicular trafficking and endocytosis of membrane receptors. The crucial function of HAP1 was further demonstrated by HAP1 knockout mice that are pbstnatally lethal and show neurodegeneration in the brain. These interesting findings raise more questions about how HAP1 is involved in the complex intracellular trafficking in neurons. Our recent studies show that HAP1 interacts with 14-3-3 and that this interaction is regulated by phosphorylation of HAP1. We hypothesize that HAP1 may link specific cargos to the microtubule transporters and that it's interactions with partners are regulated by its posttranslational modifications. Such regulation allows HAP1 to participate in intracellular transport of various cargos and endocytosis of membrane receptors. Given the idea that HAP1 dysfunction may be involved in HD pathology, it is also important to investigate if the loss of HAP1 can affect its function in intracellular trafficking. Accordingly, we propose three aims in this application.
In Aim 1, we will investigate whether 14-3-3 and phosphorylation regulate the interactions of HAP1 with microtubule transporters dynactin p150and kinesin.
In Aim -2, we will use HAP1 knockout mice and siRNA approaches to examine whether decreasing MAPI's expression alters microtubule-dependent transport and neuronal function in different types of neurons.
In Aim -3, we will study whether HAP1 deficiency affects endocytosis of membrane receptors and whether defective HAP1-associated endocytosis contributes to HD pathology. These studies aim to elucidate the function of HAP1 and to help understand the mechanisms for intracellular trafficking in neurons.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Neural Degenerative Disorders and Glial Biology Study Section (NDGB)
Program Officer
Sutherland, Margaret L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Emory University
Schools of Medicine
United States
Zip Code
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