Structural and Functional Properties of cyclophilin D and Abeta interaction.

亲环蛋白 D 和 Abeta 相互作用的结构和功能特性。

• 批准号: 8324266
• 负责人: Shirley ShiDu Yan
• 金额: $ 37.57万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8324266
• 关键词: Address; Affect; Affinity Chromatography; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Attenuated; Binding; Binding Sites; Biological; Biological Assay; Brain; Cell Death; Cell Membrane Permeability; Cells; Chemicals; Co-Immunoprecipitations; Complex; Data; Failure; Functional disorder; Generations; Goals; Immunoprecipitation; Impairment; Inner mitochondrial membrane; Isoelectric Focusing; Isotope Labeling; Lead; Learning; Ligands; Maps; Mediating; Memory; Methods; Mitochondria; Mitochondrial Matrix; Mus; NMR Spectroscopy; Neuronal Dysfunction; Neurons; Outcome; Pathogenesis; Pathway interactions; Peptides; Peptidylprolyl Isomerase; Pilot Projects; Plasma; Play; Preventive Intervention; Principal Investigator; Property; Proteins; Reactive Oxygen Species; Recombinants; Relaxation; Reporting; Research; Resolution; Respiratory Chain; Role; Site-Directed Mutagenesis; Solutions; Structure; Surface; Surface Plasmon Resonance; Synapses; System; Testing; Therapeutic Intervention; X-Ray Crystallography; base; crosslink; cyclophilin D; early onset; innovation; insight; mitochondrial dysfunction; mitochondrial membrane; mutant; neuron apoptosis; overexpression; peptide A; programs; public health relevance; synaptic function

DESCRIPTION (provided by applicant): Mitochondrial dysfunction is an early feature of Alzheimer's disease (AD). Amyloid-? peptide (A?) has deleterious effects on mitochondrial function and contributes to respiratory chain impairment, energy failure, generation of reactive oxygen species (ROS), and neuronal apoptosis in AD. Recent studies have highlighted the pivotal role of mitochondrial A? in Alzheimer's disease pathogenesis. Cyclophilin D (CypD), a peptidylprolyl isomerase F, resides in the mitochondrial matrix and associates with the inner mitochondrial membrane during the mitochondrial membrane permeability transition (mPT). CypD plays a central role in opening the mitochondrial membrane permeability transition pore (mPTP) leading to cell death. The level of CypD was significantly elevated in neurons in AD-affected regions. We have demonstrated the presence of CypD-A? complex in the cortical mitochondria of AD brain and Tg mAPP mice, and the binding of recombinant CypD protein to A? with surface plasmon resonance (SPR). CypD deficiency (lacking A? binding partner) protected against A? -mediated mitochondrial and synaptic dysfunction. Further, our pilot studies showed that increased expression of CypD (enhancing CypD- A? interaction) exacerbated mitochondrial and neuronal perturbation as well as early onset of deficits in spatial learning/memory. These studies lead us to hypothesize that CypD is a critical mitochondrial target potentiating A?-mediated mitochondrial and neuronal dysfunction. Blockade of the CypD-A? interaction will attenuate A?-induced mitochondrial and neuronal perturbation. The goal of this project is to elucidate the basis of CypD-A? interaction using crystal (Aim 1) and NMR (Aim 2) structural analyses, and to analyze critical aspects of the intracellular pathway through which engagement of CypD with A? induces mitochondrial and neuronal dysfunction (Aim 3). The proposed research is highly significant and innovative on three points. First, the expected outcomes will reveal the structural details of CypD with A? at atomic resolution, which has never been reported. Second, the consequence of CypD-A? interaction in A?-mediated mitochondrial and neuronal dysfunction will be elucidated based on structural and functional analysis. Third, the results of this proposal will have a profound impact on the AD field by establishing a new target for preventive and therapeutic intervention. PUBLIC HEALTH RELEVANCE: The goal of this project is to elucidate the basis of CypD-A? interaction using crystal and NMR structural analyses, and to analyze critical aspects of the mitochondrial pathway through which engagement of CypD with A? induces mitochondrial and neuronal damages. The results of this proposal will have a profound impact on the AD field by establishing a new target for preventive and therapeutic intervention.

描述（由申请人提供）：线粒体功能障碍是阿尔茨海默氏病（AD）的早期特征。淀粉样蛋白 - ？肽（A？）对线粒体功能有害影响，并导致呼吸链损伤，能量失效，活性氧（ROS）（ROS）和AD中的神经元凋亡。最近的研究强调了线粒体A的关键作用？在阿尔茨海默氏病发病机理中。环肽D（CYPD）是一种肽基丙基异构酶F，位于线粒体基质中，并在线粒体膜通透性过渡期间与内部线粒体膜相关联（MPT）。 CYPD在打开线粒体膜通透性过渡孔（MPTP）中起着核心作用，导致细胞死亡。在受广告影响区域的神经元中，CYPD的水平显着升高。我们已经证明了CYPD-A的存在？ AD脑和TG MAPP小鼠的皮质线粒体中的复合物，以及重组CYPD蛋白与A的结合？具有表面等离子体共振（SPR）。 CYPD缺乏症（缺乏结合伴侣）免受A的保护？ - 介导的线粒体和突触功能障碍。此外，我们的试点研究表明，CYPD的表达增加（增强CYPD- A？相互作用）加剧了线粒体和神经元扰动，以及空间学习/记忆中缺陷的早期发作。这些研究使我们假设CYPD是一个关键的线粒体靶标，它是介导的线粒体和神经元功能障碍。 CYPD-A的封锁？相互作用会减弱诱导的线粒体和神经元扰动。该项目的目标是阐明CYPD-A的基础？使用晶体（AIM 1）和NMR（AIM 2）结构分析的相互作用，并分析细胞内途径的关键方面，CYPD与A的参与度A？诱导线粒体和神经元功能障碍（AIM 3）。拟议的研究在三个方面非常重要，并且具有创新性。首先，预期的结果将揭示CYPD的结构细节？在原子分辨率上，从未报告过。第二，CYPD-A的后果？基于结构和功能分析，将阐明？介导的线粒体和神经元功能障碍中的相互作用。第三，该提案的结果将通过建立预防和治疗干预的新目标对AD领域产生深远的影响。 公共卫生相关性：该项目的目标是阐明CYPD-A的基础？使用晶体和NMR结构分析的相互作用，并分析线粒体途径的关键方面，通过哪种CYPD与A的参与？诱导线粒体和神经元损伤。该提案的结果将通过建立预防和治疗干预的新目标对广告领域产生深远的影响。