Molecular Mechanism of Wnt/Planar Cell Polarity Signaling

Wnt/平面细胞极性信号传导的分子机制

• 批准号: 10288018
• 负责人: Yingzi Yang
• 金额: $ 42.25万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-07 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10288018
• 关键词: Abeta synthesis; Administrative Supplement; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Axon; Brain; Cause of Death; Cells; Cerebral cortex; Cleaved cell; Clinical; Clinical Trials; Complex; DNA Sequence Alteration; Defect; Development; Disease; Disease Progression; Drosophila genus; Environmental Risk Factor; Epithelial; Exhibits; Foundations; Genetic; Genetic Models; Genetic study; Glutamates; Goals; Grant; Hippocampus (Brain); Immune; Impaired cognition; Investigation; Knock-in; Lesion; Mammalian Cell; Mammals; Medical; Molecular; Molecular Genetics; Mus; Mutate; Mutation; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Pathogenesis; Pathologic; Pathologic Processes; Pathology; Pathway interactions; Phosphorylation; Phosphorylation Site; Play; Production; Regulation; Research; Research Support; Role; Scheme; Senile Plaques; Signal Pathway; Signal Transduction; Skeletal Development; Solid; Synapses; Vascular Endothelium; Vertebrates; WNT Signaling Pathway; abeta accumulation; beta catenin; cognitive function; disease phenotype; extracellular; fly; genetic risk factor; in vivo; insight; mouse genetics; mouse model; mutant; neuron loss; novel; planar cell polarity; synaptogenesis; tau Proteins

Abstract Alzheimer’s disease (AD) is the most common form of neurodegenerative disorder during aging and an unmet medical challenge. AD is a complex multi-factorial disease clinically characterized by a decline in cognitive function and pathologically defined by the accumulation of extracellular β-amyloid (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). AD can be caused by both genetic defects and environmental factors and genetic mutations and risk factors have been identified that are either causal or modify the disease progression. Cellular and molecular alterations in the neuronal, astroglial, microglial/immune, and endothelial/vascular cells that modify the AD pathological hallmarks in the brain have been the focus of studies. The Wnt signaling pathways have been found to be involved causatively in the pathogenesis of AD. However, most of the research has been focused on the Wnt/b-catenin pathway. The role of the Wnt/planar cell polarity (PCP) signaling pathway in AD, though important, was understudied. The Wnt/PCP pathway is a highly conserved regulator of cellular orientation within the plane of an epithelium and has been found to be essential for brain development and function. Intriguingly, the Wnt-PCP pathway regulates axon outgrowth rather than neuronal polarity during brain development of both vertebrates and Drosophila. Despite the conservation of Wnt/PCP signaling from Drosophila to mammals, PCP regulation in vertebrates is more complex, functionally diverse and requires additional regulatory schemes and vertebrate-specific PCP component such as Ror2. It has been found that PCP signaling components play essential roles in glutamatergic synapse formation in development and Wnt/PCP signaling interacts with the amyloid precursor protein (APP) that is cleaved to become Aβ and such interaction alters Wnt/PCP signaling, which drives tau pathology and neuronal death causing AD. The majority of AD clinical trials have focused on reducing Ab load and unfortunately, these trials have been unsuccessful so far. Thus, there is an urgent need to pursue other disease modifying mechanisms and therapies. In our previous studies before and after the support of the parental grant, we have made the novel discovery for the regulation of Vangl2 phosphorylation by Wnt5a and Ror2, which exhibits fundamental difference when flies evolve to mammals. We will expand our investigation of functional requirement of Vangl2 phosphorylation in vivo in pathogenesis and progression of AD in two genetic mouse models focused respectively on APP/Ab production (5XFAD Tg6799) and tau hyper-phosphorylation (PS19). We will also determine the role of APP in Wnt5a-induced PCP signalosome. In so doing, we will gain critically important new insights into the pathophysiological mechanism underlying Wnt/PCP signaling in AD, as well as identify potential targets for manipulating Wnt/PCP signaling as an approach for AD treatment.

摘要 阿尔茨海默病（AD）是衰老期间最常见的神经退行性疾病形式，并且是一种未满足的疾病。 医学挑战AD是一种复杂的多因素疾病，临床上以认知功能下降为特征， 功能和病理学定义为细胞外β-淀粉样蛋白（Aβ）斑块和细胞内 神经原纤维缠结（NFT）。AD可由遗传缺陷和环境因素引起， 已经确定了突变和风险因素，它们是疾病进展的原因或改变疾病进展。蜂窝 以及神经元、星形胶质细胞、小胶质细胞/免疫细胞和内皮/血管细胞的分子改变， 改变AD的脑病理标志一直是研究的重点。Wnt信号通路 已发现其与AD的发病机制有关。然而，大多数研究都是 集中在Wnt/β-连环蛋白通路上。Wnt/平面细胞极性（PCP）信号通路在AD中的作用， 虽然重要，但被低估了。Wnt/PCP通路是一种高度保守的细胞定向调节因子 在上皮的平面内，并且已经发现对于脑发育和功能是必需的。 有趣的是，Wnt-PCP通路在大脑发育过程中调节轴突生长，而不是神经元极性。 脊椎动物和果蝇的发展。尽管果蝇的Wnt/PCP信号转导保守， 与哺乳动物相比，脊椎动物对五氯苯酚的调节更为复杂，功能多样，需要额外的 监管计划和脊椎动物特有的五氯苯酚成分，如Ror 2。已经发现PCP信号传导 在发育过程中的突触形成和Wnt/PCP信号传导中起重要作用 与淀粉样前体蛋白（APP）相互作用，APP被切割成Aβ，这种相互作用改变了 Wnt/PCP信号传导，其驱动tau病理和神经元死亡，导致AD。大多数AD临床试验 一直专注于减少抗体负荷，不幸的是，这些试验迄今为止都不成功。由此可见，有 迫切需要寻求其他疾病修饰机制和疗法。在我们之前的研究中， 在获得了亲本基金的支持后，我们对Vangl 2的调控有了新的发现 Wnt 5a和Ror 2的磷酸化，这在果蝇进化为哺乳动物时表现出根本性的差异。我们 将扩展我们对Vangl 2磷酸化在发病机制中的体内功能需求的研究， 两种遗传小鼠模型中的AD进展分别集中于APP/Ab产生（5XFAD Tg 6799） 和tau过度磷酸化（PS19）。我们还将确定APP在Wnt 5a诱导的PCP中的作用。 信号体这样做，我们将获得至关重要的新见解的病理生理机制 AD中潜在的Wnt/PCP信号传导，以及识别操纵Wnt/PCP信号传导的潜在靶点， 一种治疗AD的方法