Neuronal function of huntingtin-associated protein Huntingtin-associated protein-1 (Hap1) was first identified as a neuronal protein that interacts with the Huntington's disease (HD) protein, huntingtin (Htt). Hap1's binding to Htt is enhanced by expanded polyglutamine repeats in the N-terminal region of Htt. Moreover, unlike Htt, which is ubiquitously expressed, Hap1 is expressed primarily in neuronal cells, suggesting that it is a good candidate for involvement in the selective neurodegeneration in HD. Extensive studies have shown that Hap1 and Htt associate with each other in the intracellular trafficking of various vesicles and proteins. Also, like Htt, Hap1 is essential for early development and neurogenesis. Our recent studies showed that the function of both Hap1 and Htt is cell type and age dependent. We also know that neurogenesis is important for early brain development and the repair of neuronal damage in the adult brain. Although both Htt and Hap1 participate in neurogenesis, and impaired neurogenesis is seen in HD brains, whether Hap1 and Htt work together to regulate neurogenesis and whether mutant Htt affects neurogenesis via its interaction with Hap1 remain unknown. We hypothesize that Hap1 and Htt participate in age- and environmental stress-dependent neurogenesis and that mutant Htt affects this function by its interaction with Hap1. To test this hypothesis, we will use Hap1 KO and Htt KO mice as well as HD140Q knock-in mice to examine the role of the interaction of Hap1 and Htt in postnatal and adult neurogenesis. We will focus on neurogenesis in the hypothalamus and hippocampus, as loss of Hap1 in these two regions is found to cause body weight loss and depression, two well-known phenotypes that also occur in HD patients. We will use CRISPR/Cas9 to selectively deplete Htt expression or to increase the production of N-terminal mutant Htt in HD140Q KI mice to examine whether they have any effects on neurogenesis. Using these approaches, we propose two aims in this application.
Aim 1 will investigate whether Hap1 and Htt work together to promote neurogenesis.
Aim 2 will explore whether mutant Htt affects neurogenesis via its abnormal interaction with Hap1. The studies seek to provide new insight into the cell type- and age-dependent function of Hap1 and Htt, as well as the selective neuropathology of HD. Findings from these studies will also help us uncover therapeutic strategies for the specific neuropathology and phenotypes in HD. !
Huntington disease is caused by expansion of a polyglutamine repeat in the N-terminal region of huntingtin. We will investigate whether Hap1, a huntingtin associated protein, and huntingtin work together to regulate neurogenesis and whether mutant huntingtin affects neurogenesis via its abnormal interaction with Hap1, aiming to identify cell-type dependent pathology in Huntington disease.
|Yan, Sen; Tu, Zhuchi; Li, Shihua et al. (2018) Use of CRISPR/Cas9 to model brain diseases. Prog Neuropsychopharmacol Biol Psychiatry 81:488-492|
|Lim, Yoon; Wu, Linda Lin-Yan; Chen, Si et al. (2018) HAP1 Is Required for Endocytosis and Signalling of BDNF and Its Receptors in Neurons. Mol Neurobiol 55:1815-1830|
|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|
|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; Yang, Huiming; Chang, Renbao et al. (2017) MANF regulates hypothalamic control of food intake and body weight. Nat Commun 8:579|
|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|
|Li, Xiao-Jiang; Tu, Zhuchi; Yang, Weili et al. (2017) CRISPR: Established Editor of Human Embryos? Cell Stem Cell 21:295-296|
|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|
|Cui, Yiting; Yang, Su; Li, Xiao-Jiang et al. (2017) Genetically modified rodent models of SCA17. J Neurosci Res 95:1540-1547|
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