Tau-PI3Kalpha Complex in Regulation of PI3K/Akt-dependent Neuronal Function and Survival
Tau-PI3Kalpha Complex in Regulation of PI3K/Akt-dependent Neuronal Function and Survival
批准号:
10710161
负责人:
Richard A. Anderson
金额:
$19.27万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
已结题
起止时间:
2022-09-30 至 2024-05-31
关键词:
AffectAffinityAgingAlzheimer&aposs DiseaseAmino AcidsAxonAxonal TransportBindingCell CommunicationCell DeathCell LineCell SurvivalCell physiologyCellsComplexDataDendritesDiseaseDisease ProgressionEndosomesFRAP1 geneFluorescein-5-isothiocyanateFoundationsGenerationsGrowth FactorHippocampusImpairmentIn VitroInduced pluripotent stem cell derived neuronsInsulinInsulin ReceptorInvestigationLabelLinkMAP4MAPT geneMapsMediatingMicrotubulesModelingMolecularMutateMutationNeurodegenerative DisordersNeurofibrillary TanglesNeuronsNuclear Magnetic ResonancePI3 genePIK3CG genePathogenicityPathologicPathologyPeptidesPermeabilityPharmaceutical PreparationsPhosphorylationPhosphotransferasesPlayReceptor Protein-Tyrosine KinasesRegulationRoleSignal PathwaySignal TransductionSiteSmall Interfering RNASpatial DistributionStructureTauopathiesTestingTherapeuticWorkhyperphosphorylated tauin vivoinsulin signalingknock-downmutantneurofibrillary tangle formationneuron lossneuronal survivalneurotoxicityneurotransmissionreceptorscaffoldtau Proteinstau aggregationtau interactiontau microtubule binding domaintau mutationtau-1therapeutic development
中文摘要
项目总结
包括阿尔茨海默病在内的tau病理是最常见和最复杂的神经退行性疾病
到2050年,全球老龄化人口可能达到1.15亿(6),但目前还没有治疗这种疾病的治疗药物
疾病,除了最近批准的一种有争议的药物(7)。通过细胞内神经原纤维的形成
皮层和海马区过度磷酸化的tau蛋白的缠结(NFT)是一个关键
Tau病理的病理特征,即过度磷酸化tau如何影响的确切机制
神经元中缺乏生存信号。最近我们发现PI3K/Akt生存信号
通路由直接相互作用的非神经元型微管相关蛋白4(MAP4)控制
与PI3K通过其微管结合域(MTBD)结合(9)。PI3K与MAP4的相互作用控制PI3K
与PI3K激活、PI3、4、5P3生成所需的激活受体激酶的关联
AKT激活(9例)。与PI3K结合的MAP4的MTBD与微管有很高的同源性-
神经元微管相关蛋白tau和MAP2的结合域,刺激了以下假设
Tau和MAP2替代MAP4控制神经元中的PI3K/Akt生存信号。我们的初步数据显示
Tau和PI3K在原代神经元、诱导的多能干细胞来源的神经元中的联系,以及
一种神经细胞系。SiRNA介导的tau基因敲除阻断了胰岛素刺激Akt的激活。
我们假设tau是沿着轴突和树突中的微管将pi3k作为支架来控制生长因子的。
刺激神经元PI3K/Akt存活信号。Tau蛋白过度磷酸化及其聚集增加
在阿尔茨海默病期间,进展损害了PI3K沿微管的空间组织,导致
在缺失生长因子的刺激下,PI3K/Akt信号通路对神经细胞的生存和功能至关重要。
建议的研究重点是从机制上建立和理解tau在PI3K/Akt信号转导中的作用
并定义了tau中的pi3k相互作用位点。PI3K和Tau之间的相互作用将被用来定义
PI3K在tau病中的相互作用位点及其与致病突变的关系
和tau基因MTBD中的过度磷酸化位点。我们将定义tau损失对空间分布的影响,
PI3K与激活受体在轴突和树突中的共存、相互作用及其对生长的影响
因子刺激PI3、4、5P3的产生和Akt的激活。这一点将通过系统性的
表达缺失tau基因对PI3K结合的影响及对PI3K DNA结合的破坏作用
细胞通透性多肽对PI3K/信号转导和神经元存活的影响
英文摘要
PROJECT SUMMARY
Tau pathologies including Alzheimer’s disease are the most prevalent and complex neurodegenerative diseases
of aging that will likely reach 115 million globally by 2050(6) yet, there are no therapeutic drugs to treat this
disease, except a controversial recently approved drug(7). Though the formation of intracellular neurofibrillary
tangles (NFTs) from the hyperphosphorylated tau protein in the cortical and hippocampal regions is a key
pathological hallmark of tau pathologies, the precise mechanisms of how hyperphosphorylated tau impact
survival signaling in neurons is lacking. Recently we have shown that the PI3K/Akt survival signaling
pathway is controlled by the non-neuronal type microtubule-associated protein 4 (MAP4) that directly interacts
with PI3K via its microtubule-binding domain (MTBD)(9). The PI3K interaction with MAP4 controls the PI3K
association with activated receptor kinases that are required for PI3K activation, PI3,4,5P3 generation, and
Akt activation(9). The MTBD of MAP4 that binds PI3K shows strikingly high homology with the microtubule-
binding domain of the neuronal microtubule-associated proteins tau and MAP2, stimulating the hypothesis that
tau and MAP2 substitute for MAP4 control of PI3K/Akt survival signaling in neurons. Our preliminary data shows
the association between tau and PI3K in primary neurons, induced pluripotent stem cells-derived neurons, and
a neuronal cell line. The siRNA-mediated knockdown of tau blocked insulin stimulated Akt activation.
We hypothesize that tau scaffold the PI3K along microtubules in axons and dendrites to control growth factor
stimulated PI3K/Akt survival signaling of neurons. Increased tau hyperphosphorylation and its aggregation
during Alzheimer’s disease progression impairs the spatial organization of PI3K along microtubules resulting
in loss of growth factor stimulated PI3K/Akt signaling that is critical for neuronal cell survival and function.
The focus of proposed study is to establish and understand mechanistically tau’s role in the PI3K/Akt signaling
and define the PI3K interaction sites in tau. The interaction between PI3K and tau will be used to define the
interaction sites for PI3K in the MTBD of tau and investigate if these sites coincide with pathogenic mutants
and hyperphosphorylation sites in the MTBD of tau. We will define the effect of tau loss on spatial distribution,
co-localization and interaction of PI3K with activated receptors in axons and dendrites, and effect on growth
factor stimulated PI3,4,5P3 generation and Akt activation. This will be further substantiated by a systemic
investigation of the impact of expressing mutant tau that is deficient on PI3K binding and the disruption of
PI3K-tau interaction by cell permeable peptides on spatial PI3K/Akt signaling and survival of neurons.
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