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.
|Xiang, Jianxing; Yang, Su; Xin, Ning et al. (2017) DYRK1A regulates Hap1-Dcaf7/WDR68 binding with implication for delayed growth in Down syndrome. Proc Natl Acad Sci U S A 114:E1224-E1233|
|Cui, Yiting; Yang, Su; Li, Xiao-Jiang et al. (2017) Genetically modified rodent models of SCA17. J Neurosci Res 95:1540-1547|
|Yang, Su; Yang, Huiming; Chang, Renbao et al. (2017) MANF regulates hypothalamic control of food intake and body weight. Nat Commun 8:579|
|Li, Xiao-Jiang; Tu, Zhuchi; Yang, Weili et al. (2017) CRISPR: Established Editor of Human Embryos? Cell Stem Cell 21:295-296|
|Zhao, Ting; Hong, Yan; Yin, Peng et al. (2017) Differential HspBP1 expression accounts for the greater vulnerability of neurons than astrocytes to misfolded proteins. Proc Natl Acad Sci U S A 114:E7803-E7811|
|Tu, Zhuchi; Yang, Weili; Yan, Sen et al. (2017) Promoting Cas9 degradation reduces mosaic mutations in non-human primate embryos. Sci Rep 7:42081|
|Yang, Su; Chang, Renbao; Yang, Huiming et al. (2017) CRISPR/Cas9-mediated gene editing ameliorates neurotoxicity in mouse model of Huntington's disease. J Clin Invest 127:2719-2724|
|Yang, Yang; Yang, Su; Guo, Jifeng et al. (2017) Synergistic Toxicity of Polyglutamine-Expanded TATA-Binding Protein in Glia and Neuronal Cells: Therapeutic Implications for Spinocerebellar Ataxia 17. J Neurosci 37:9101-9115|
|Hong, Yan; Zhao, Ting; Li, Xiao-Jiang et al. (2017) Mutant Huntingtin Inhibits ?B-Crystallin Expression and Impairs Exosome Secretion from Astrocytes. J Neurosci 37:9550-9563|
|Lim, Yoon; Wu, Linda Lin-Yan; Chen, Si et al. (2017) HAP1 Is Required for Endocytosis and Signalling of BDNF and Its Receptors in Neurons. Mol Neurobiol :|
Showing the most recent 10 out of 75 publications