ER SIGNAL AND CHAPERONE-MEDIATED AUTOPHAGY IN NEURONAL STRESS

神经元应激中的 ER 信号和伴侣介导的自噬

• 批准号: 9240687
• 负责人: ZIXU MAO
• 金额: $ 34.13万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-15 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9240687
• 关键词: Acute; Alzheimer' s Disease; Attenuated; Autophagocytosis; Calcium; Cell Death Signaling Process; Cell Line; Cell physiology; Cells; Cessation of life; Chronic; Coupling; Critical Pathways; Data; Development; Disease; Endoplasmic Reticulum; Enhancers; FRAP1 gene; Face; Failure; Functional disorder; Genetic Models; Hippocampus (Brain); Homeostasis; Human; Impairment; In Vitro; Individual; Injury; Knowledge; Laboratories; Lead; Link; Lysosomes; MAP Kinase Gene; MAPK14 gene; Mammalian Cell; Mediating; Mediator of activation protein; Membrane Proteins; Methods; Mitochondria; Mitogen-Activated Protein Kinase Inhibitor; Modeling; Molecular; Molecular Chaperones; Muscle Cells; Names; Nerve Degeneration; Neurodegenerative Disorders; Neurologic Process; Neuronal Injury; Neurons; Organelles; Outcome; Oxides; Parkinson Disease; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Play; Population; Process; Proteins; Reaction; Regulation; Regulatory Pathway; Research; Role; Signal Pathway; Signal Transduction; Site; Stress; Stroke; System; Testing; Tissues; biological adaptation to stress; brain tissue; chronic neurologic disease; design; effective therapy; endoplasmic reticulum stress; in vivo; innovation; insight; nervous system disorder; neuron loss; neuronal survival; neuroprotection; neurotoxic; neurotoxicity; novel; novel therapeutic intervention; novel therapeutics; pars compacta; protein folding; public health relevance; response; secretory protein; sensor; transcription factor

DESCRIPTION (provided by applicant): Neurons, when faced with endogenous and exogenous insults, mobilize their network of machinery to relief stress. Failure of this attempt often results in neuronal death. Many human neurological diseases such as Alzheimer's and Parkinson's diseases are characterized by the pathological loss of neurons. The long-term objective of our research is to understand how neurons respond to stress and the role of dysfunction of survival response in neurodegenerative process. We propose in this application to study a novel link between endoplasmic reticulum (ER) and lysosomes, two key organelles responsible for handling stress and maintaining cellular homeostasis, in neuronal stress response and in neurodegenerative process. Studies indicate that many toxic signals perturb ER homeostasis. Correcting ER stress requires the activation of multiple ER signal pathways. However, prolonged stress may also direct ER to generate cell death signals. There is strong evidence to implicate the dysfunction of ER stress response in both acute and chronic neurological diseases. Lysosomes participate in maintaining neuronal homeostasis by degrading intracellular constitutes in response to stress, a process named autophagy. Chaperone-mediated autophagy (CMA) is distinct from the traditional macroautophagy in that CMA selectively degrades individual proteins. CMA is critical since nearly 30% of cytosolic proteins contain the conserved motif recognized by CMA and are potential regulatory targets. Recent studies suggest that dysfunction of CMA plays an important role in neuronal stress and neurological diseases. Despite their respective roles in handling neuronal stress, it is not known whether ER stress and CMA are linked. Our recent studies showed that the nonfunctional form of neuronal survival protein, myocyte enhancer factor 2D (MEF2D), is degraded by CMA and disruption of this regulatory process underlies neuronal stress and occurs in models of Parkinson's diseases. Our preliminary studies indicate that ER stress leads to MEF2D degradation, which is dependent on CMA and requires p38 MAPK, a well-known stress sensor. Together, these intriguing data support an exciting hypothesis that ER stress activates CMA via a p38 dependent mechanism. We will combine molecular and cellular methods and use in vivo and genetic models to determine in Aim I, the role of p38 MAPK in ER stress-mediated activation of CMA in neurons; in Aim II, the mechanisms by which p38 senses ER stress and activates CMA; and in Aim III, the role of ER stress-p38-CMA pathway in neuronal viability. This study will establish a novel link between two key processes, ER stress and lysosomal CMA, reveal the stress sensor p38 MAPK as the mediator, uncover the molecular mechanism(s) underlying this regulatory pathway, and establish a functional role for this network in neuronal stress and survival. This new mechanistic network should be highly relevant to the pathogenic process of neurological diseases and may aid the development of novel therapeutic strategies.

描述（由申请人提供）：神经元在面临内源性和外源性攻击时，会调动其机器网络来缓解压力。这种尝试的失败通常会导致神经元死亡。许多人类神经系统疾病，例如阿尔茨海默病和帕金森病，其特征是神经元的病理性丢失。我们研究的长期目标是了解神经元如何应对压力以及生存反应功能障碍在神经退行性过程中的作用。我们建议在本申请中研究内质网（ER）和溶酶体之间的新联系，这两种关键细胞器在神经元应激反应和神经退行性过程中负责处理应激和维持细胞稳态。研究表明许多有毒信号会扰乱内质网稳态。纠正内质网应激需要激活多个内质网信号通路。然而，长时间的压力也可能导致内质网产生细胞死亡信号。有强有力的证据表明急性和慢性神经系统疾病中内质网应激反应的功能障碍。溶酶体通过响应应激而降解细胞内成分，参与维持神经元稳态，这一过程称为自噬。伴侣介导的自噬 (CMA) 与传统的巨自噬不同，CMA 选择性降解单个蛋白质。 CMA 至关重要，因为近 30% 的胞质蛋白含有 CMA 识别的保守基序，并且是潜在的监管目标。最近的研究表明，CMA 功能障碍在神经元应激和神经系统疾病中起着重要作用。尽管 ER 应激和 CMA 在处理神经元应激方面各自发挥作用，但尚不清楚它们是否相关。我们最近的研究表明，神经元存活蛋白的非功能形式，即肌细胞增强因子 2D (MEF2D)，会被 CMA 降解，而这种调节过程的破坏是神经元应激的基础，并发生在帕金森病模型中。我们的初步研究表明，ER 应激会导致 MEF2D 降解，这依赖于 CMA，并且需要 p38 MAPK（一种众所周知的应激传感器）。总之，这些有趣的数据支持了一个令人兴奋的假设，即 ER 应激通过 p38 依赖性机制激活 CMA。我们将结合分子和细胞方法，并使用体内和遗传模型来确定 Aim I 中 p38 MAPK 在神经元中 ER 应激介导的 CMA 激活中的作用；在目标 II 中，p38 感知 ER 应激并激活 CMA 的机制；在目标 III 中，ER 应激-p38-CMA 通路在神经元活力中的作用。这项研究将在 ER 应激和溶酶体 CMA 这两个关键过程之间建立新的联系，揭示应激传感器 p38 MAPK 作为介质，揭示该调节途径的分子机制，并确定该网络在神经元应激和生存中的功能作用。这种新的机制网络应该与神经系统疾病的发病过程高度相关，并可能有助于开发新的治疗策略。