Role of phosphoinositides in neuronal membrane traffic and neurodegeneration

磷酸肌醇在神经元膜交通和神经变性中的作用

• 批准号: 8372410
• 负责人: Gilbert Di Paolo
• 金额: $ 34.71万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8372410
• 关键词: Ablation; Address; Affect; Alzheimer' s Disease; Amyloid beta-Protein Precursor; Animal Model; Apolipoprotein E; Autophagocytosis; Autophagosome; Binding; Biogenesis; Biology; Brain; Brain region; Cell physiology; Cells; Cellular Membrane; Cholesterol Homeostasis; Chronic; Data; Defect; Disease; Embryo; Endosomes; Engineering; Enzymes; Fibroblasts; Functional disorder; Genetic; Gifts; Goals; Hippocampus (Brain); Human; Impaired cognition; Individual; Integral Membrane Protein; Knockout Mice; Late Onset Alzheimer Disease; Life; Link; Lipids; Lysine; Mediating; Membrane; Membrane Protein Traffic; Metabolism; Molecular; Mus; Mutagenesis; Mutation; Nerve Degeneration; Neurons; Organelles; Organism; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Phenotype; Phosphatidylinositols; Phosphotransferases; Play; Prefrontal Cortex; Process; Prosencephalon; Role; Sampling; Signal Transduction; Sorting - Cell Movement; Synapses; System; Testing; Tissues; Transgenes; Transgenic Animals; Ubiquitination; Vesicle; Work; amyloid precursor protein processing; amyloidogenesis; base; brain tissue; endosome membrane; entorhinal cortex; familial Alzheimer disease; human disease; in vivo; insight; interdisciplinary approach; knock-down; men; mouse model; mutant; neuron loss; phosphatidylinositol 3-phosphate; protein complex; protein degradation; secretase; tau Proteins; tau aggregation; tool; trafficking

DESCRIPTION (provided by applicant): Intracellular signaling lipids control a large variety of cellular processes, including membrane trafficking, cytoskeletal dynamics, transport across membranes and signal transduction. Not surprisingly, lipid signaling and alterations thereof are increasingly linked to human disease. Alzheimer's disease (AD) is one such disorder in which lipid dyshomeostasis and membrane trafficking defects are believed to play a critical role. This concept is easily reconciled with the fact that the main molecular players in AD, including amyloid precursor protein (APP) and the ?-, ?- and ?-secretases, are all transmembrane proteins (or protein complexes) that traffic in cells and exert their functions at or within cellulr membranes. Our working hypothesis is that specific lipid changes may drive or mediate fundamental aspects of AD pathogenesis. Systems-based approaches, such as "lipidomics", are emerging as a powerful tool to profile cells, tissues or organisms in a diseased state, providing both an unbiased and comprehensive picture of lipid alterations potentially linked to pathogenicity. To better understand the link between lipid signaling defects and AD pathogenesis, we have recently conducted a lipidomic analysis of brain samples derived from three transgenic animal models of familial AD as well as three independent brain regions from patients with late-onset AD. We found that out of 330 lipid species analyzed, only one lipid species was significantly reduced in AD-affected brain regions in mice (forebrain) and men (entorhinal and prefrontal cortex): phosphatidylinositol-3-phosphate (PI3P). PI3P is a phosphoinositide primarily synthesized by lipid kinase Vps34 and acts as a master regulator of the endosomal and autophagy pathways. PI3P controls the recruitment of a variety of compartment-specific effectors harboring PI3P binding modules, such as FYVE or PX domains. We found that knocking down/out Vps34 recapitulates salient features linked to AD pathogenesis, namely (i) enlarged endosomes; (ii) aberrant endosomal trafficking and processing of the amyloid precursor protein (APP); and (iii) accumulation of autophagy substrates. Additionally, work from others shows that chronic lack of Vps34 in neurons produces neurodegeneration. Altogether, our results have identified PI3P deficiency as a key factor in AD pathogenesis. This proposal focuses on addressing the consequences of disrupting PI3P signaling on two processes that emerge as critical in AD pathogenesis, namely the endosomal trafficking and processing of APP (Aim 1) and neuronal autophagy (Aim 2). It will also assess the impact of PI3P deficiency on the A? and Tau pathologies in vivo (Aim 3). We anticipate that our studies will provide key insights into the biology of APP and Tau as well as a better understanding of the role of lipid dysregulation in AD pathogenesis. PUBLIC HEALTH RELEVANCE: Lipid dysregulation is believed to play an important role in the pathogenesis of Alzheimer's disease (AD). Our lipidomic analyses of brain tissue derived from mouse models of AD and AD-affected individuals have identified phosphatidylinositol-3-phosphate (PI3P) deficiency as a candidate lipid alteration involved in AD pathogenesis. The goal of the proposed studies is to test the role of PI3P and a key enzyme mediating its synthesis, Vps34, in the traffic of amyloid precursor protein and the clearance of tau aggregates.

描述（由申请人提供）：细胞内信号传导脂质控制着各种各样的细胞过程，包括膜运输，细胞骨架动力学，跨膜的传输和信号转导。毫不奇怪，脂质信号传导及其改变与人类疾病越来越多。阿尔茨海默氏病（AD）是一种这样的疾病，其中脂肪dyshomeostasis和膜贩运缺陷被认为起着至关重要的作用。这个概念很容易与AD中的主要分子参与者（包括淀粉样蛋白前体蛋白（APP）和？ - ，？ - 和？ - 分泌酶，所有跨膜蛋白（或蛋白质络合物）都在细胞中流动并在纤维膜内或在纤维膜内发挥功能。我们的工作假设是，特定的脂质变化可能会驱动或介导AD发病机理的基本方面。基于系统的方法（例如“脂肪态学”）正在成为病态状态下细胞，组织或生物的强大工具，从而提供了与致病性有关的脂质改变的无偏见和全面的图片。为了更好地理解脂质信号传导缺陷与AD发病机理之间的联系，我们最近对源自家族性AD的三种转基因动物模型以及来自晚期AD患者的三个独立大脑区域进行了脂肪组分析。我们发现，在分析的330种脂质物种中，在小鼠（前脑）和男性（室内和前额叶皮层）中，只有一种脂质物种显着降低：磷脂酰迪辛 - 3-磷酸（PI3P）。 PI3P是一种主要由脂质激酶VPS34合成的磷酸肌醇，并充当内体和自噬途径的主调节剂。 PI3P控制着具有PI3P结合模块（例如FYVE或PX域）的各种隔室特异性效应器的募集。我们发现，将VPS34击倒/击倒VPS34概括了与AD发病机理有关的显着特征，即（i）增大的内体。 （ii）淀粉样蛋白蛋白（APP）的异常内体贩运和加工； （iii）自噬底物的积累。此外，其他工作表明，神经元中慢性缺乏VPS34会产生神经变性。总之，我们的结果已将PI3P缺乏症确定为AD发病机理的关键因素。该提议着重于解决在AD发病机理至关重要的两个过程中破坏PI3P信号传导的后果，即APP的内体贩运和处理（AIM 1）和神经元自噬（AIM 2）。它还将评估PI3P缺陷对A的影响？和体内的tau病理学（AIM 3）。我们预计我们的研究将为APP和TAU的生物学提供关键的见解，并更好地了解脂质失调在AD发病机理中的作用。 公共卫生相关性：据信脂质失调在阿尔茨海默氏病（AD）的发病机理中起重要作用。我们对源自AD和受AD影响个体的小鼠模型的脑组织的脂肪组分析已鉴定出磷脂酰肌醇-3-磷酸（PI3P）缺乏症是参与AD发病机理的候选脂质改变。拟议的研究的目的是测试PI3P和介导其合成VPS34的关键酶在淀粉样蛋白前体蛋白质和Tau聚集体的清除率中的作用。