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The roles of Huntingtin Associated Protein 40 in Huntingtin functions and Huntingtons disease pathogenesis

亨廷顿相关蛋白 40 在亨廷顿功能和亨廷顿病发病机制中的作用

基本信息

批准号：
10608221
负责人：
Sheng Zhang
金额：
$ 7.6万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10608221
关键词：
Affect Affinity Chromatography Animal Model Animals Autophagocytosis Binding Biochemical Biological Assay Brain Cell physiology Cells Complex Corpus striatum structure Development Disease Disease model Distant Drosophila genus Drug Targeting Etiology Evaluation Evolution Experimental Models Fibroblasts Foundations Genes Genetic Genetic Models Genetic Transcription Glutamine Health Heterogeneity Homologous Gene Human Huntington Disease Huntington gene Huntington protein Knock-out Lead Mammalian Cell Mammals Molecular Molecular Conformation Mus Mutate Mutation Neurons Pathogenesis Pathogenicity Patients Phenotype Physiological Prevention Proteins Proteomics Rattus Regulation Reporting Role Sampling Scaffolding Protein Sequence Alignment Structure Testing Tissues Toxic effect fly gain of function genetic testing in vivo knockout animal loss of function multidisciplinary mutant neuronal survival neurotoxicity novel novel therapeutics overexpression polyglutamine vesicle transport

项目摘要

Huntington's disease (HD) is caused by an abnormal expansion of the glutamine tract (polyQ) in Huntingtin (HTT). A clear understanding on how endogenous HTT is regulated in vivo is critical both for elucidating HD etiology and for identifying effective drug targets. HTT has numerous reported HTT associated partners (HAPs) and is functionally implicated in a growing list of cellular processes. However, little is known how HTT itself is regulated and whether such regulation is altered in HD. We previously characterized the HTT homolog (dHtt) in model organism Drosophila. Given the significant functional conservation of HTT from the fly to mammals, we hypothesized that the core regulators of HTT likely are among the numerous known HAPs and should also be conserved in Drosophila. In a proteomic study for such conserved central regulators of HTT in Drosophila, we isolated dHap40, the fly homolog of HAP40, as the strongest dHtt interactor. Importantly, converging evidence from studies in multiple species all support that in vivo HTT protein normally exists in a complex with HAP40, and HAP40 binding stabilizes the conformation of HTT. Further, in samples from HD patients, a ~10- fold increase of the levels of endogenous HAP40 were observed as compared to controls. However, despite these findings, by now there is no reported functional study of HAP40 in any physiological settings, and its effect on HTT's normal functions and mutant HTT toxicity remains unclear. Our preliminary studies support the significantly conserved physical and functional interactions between HTT and HAP40, implying a highly important regulatory relationship that constrains their co-evolution from flies to humans. Our findings not only establish Drosophila as a relevant genetic model to study the physiological roles of HAP40, but also lead to our hypothesis that HAP40 is a conserved central regulator of HTT and potentially a critical modulator of mutant HTT toxicity. Using established assays and HD models in Drosophila and cultured mammalian cells, we will systematically test this hypothesis. In Aim 1, we will carry out a comprehensive phenotypic analyses of dhap40 gene and test its genetic interactions with dhtt, so as to obtain a first systematic evaluation of HAP40 in a physiological setting and clarify its relationship with HTT at whole-animal level. In Aim 2, we will systematically test whether HAP40 is a central regulator of HTT's subcellular dynamics and its diverse cellular functions, so as to elucidate its relationship with HTT at molecular and cellular levels. In Aim 3, taking advantage of the well- established HD models in Drosophila and mammalian neurons, we will rigorously interrogate the role of HAP40 on mutant HTT toxicity. From these multidisciplinary studies, we will obtain a first comprehensive evaluation on the physiological functions of HAP40, its effect on endogenous HTT functions and on HD pathogenesis. The results potentially lay foundation on novel therapeutic avenues against HD via HAP40.

亨廷顿舞蹈病（HD）是由亨廷顿蛋白中谷氨酰胺束（polyQ）的异常扩张引起的