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

基本信息

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
项目类别：
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&apos 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

项目摘要

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）：当面对内源性和外源性侮辱时，神经元动员其机械网络以减轻压力。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，例如阿尔茨海默氏症和帕金森氏症的疾病，其特征是神经元的病理丧失。我们研究的长期目标是了解神经元如何应对压力和生存反应功能障碍在神经退行性过程中的作用。我们在此应用中建议研究内质网（ER）和溶酶体之间的新联系，这是两个负责处理压力和维持细胞稳态的关键细胞器，在神经元应力反应和神经退行性过程中。研究表明，许多有毒信号扰动ER稳态。校正ER应力需要激活多个ER信号途径。但是，延长的压力也可能导致ER产生细胞死亡信号。有强有力的证据表明在急性和慢性神经系统疾病中，ER应激反应的功能障碍。溶酶体通过降解细胞内构成压力（一种称为自噬的过程）来维持神经元稳态。伴侣介导的自噬（CMA）与传统的大型噬菌学不同，因为CMA有选择地降解单个蛋白质。 CMA至关重要，因为将近30％的胞质蛋白包含CMA识别的保守基序，并且是潜在的调节靶标。最近的研究表明，CMA功能障碍在神经元压力和神经系统疾病中起重要作用。尽管它们在处理神经元压力方面的作用各自，但尚不清楚ER应力和CMA是否连接。我们最近的研究表明，神经元存活蛋白的非功能形式，肌细胞增强子因子2d（MEF2D）被CMA降解，并且这种调节过程的破坏是神经元应激的基础，并发生在帕金森氏病模型中。我们的初步研究表明，ER应力会导致MEF2D降解，这取决于CMA，并且需要p38 MAPK（一种众所周知的应力传感器）。这些有趣的数据共同支持了令人兴奋的假设，即ER应力通过p38依赖机制激活CMA。我们将结合分子和细胞方法，并在体内和遗传模型中使用AIM I（p38 MAPK在神经元中CMA的激活中）的作用；在AIM II中，p38感觉到ER应力并激活CMA的机制；在AIM III中，ER应力-P38-CMA途径在神经元活力中的作用。这项研究将在两个关键过程（ER应力和溶酶体CMA）之间建立新的联系，揭示了应力传感器p38 MAPK作为介体，揭示了该调节途径的分子机制，并确定了该网络在神经元应力和存活中的功能作用。这个新的机械网络应与神经疾病的致病过程高度相关，并可能有助于发展新型治疗策略。