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多种细胞过程，包括膜运输、细胞骨架动力学、跨膜转运和信号转导。毫不奇怪，脂质信号传导及其改变越来越多地与人类疾病相关。阿尔茨海默病（AD）是其中脂质稳态异常和膜运输缺陷被认为起关键作用的一种这样的病症。这一概念很容易与AD中的主要分子参与者，包括淀粉样前体蛋白（APP）和β-，?-然后呢？分泌酶是所有跨膜蛋白（或蛋白复合物），其在细胞中运输并在细胞膜处或细胞膜内发挥其功能。我们的工作假设是，特定的脂质变化可能会驱动或介导AD发病机制的基本方面。基于系统的方法，例如“脂质组学”，正在成为描述处于患病状态的细胞、组织或生物体的强大工具，提供了可能与致病性相关的脂质变化的公正而全面的情况。为了更好地了解脂质信号传导缺陷和AD发病机制之间的联系，我们最近对来自三个家族性AD转基因动物模型的脑样本以及来自迟发性AD患者的三个独立脑区域进行了脂质组学分析。我们发现，在分析的330种脂质中，只有一种脂质在小鼠（前脑）和男性（内嗅和前额皮质）的AD影响的大脑区域中显着减少：磷脂酰肌醇-3-磷酸（PI 3 P）。PI 3 P是主要由脂质激酶Vps 34合成的磷酸肌醇，并作为内体和自噬途径的主要调节剂。PI 3 P控制包含PI 3 P结合模块（如FYVE或PX结构域）的多种区室特异性效应物的募集。我们发现敲低/敲除Vps 34概括了与AD发病机制相关的显著特征，即（i）扩大的内体;（ii）淀粉样前体蛋白（APP）的异常内体运输和加工;和（iii）自噬底物的积累。此外，其他人的工作表明，神经元中长期缺乏Vps 34会导致神经变性。总之，我们的研究结果表明，PI 3 P缺乏是AD发病机制的关键因素。该提案的重点是解决在AD发病机制中出现的两个关键过程中破坏PI 3 P信号传导的后果，即APP的内体运输和加工（目的1）和神经元自噬（目的2）。它还将评估PI 3 P缺乏对A？和体内Tau病理学（目的3）。我们预计，我们的研究将为APP和Tau的生物学提供关键见解，并更好地了解脂质失调在AD发病机制中的作用。 公共卫生相关性：脂质失调被认为在阿尔茨海默病（AD）的发病机制中起重要作用。我们的脂质组学分析来自小鼠模型的AD和AD受影响的个人的脑组织已确定磷脂酰肌醇-3-磷酸（PI 3 P）缺乏症作为一个候选人参与AD发病机制的脂质改变。拟议研究的目标是测试PI 3 P和介导其合成的关键酶Vps 34在淀粉样前体蛋白的运输和tau聚集体的清除中的作用。