A Novel Role of Fragile-X Mental Retardation Protein in Mitochondrial Calcium Homeostasis

Fragile-X 智力迟钝蛋白在线粒体钙稳态中的新作用

基本信息

批准号：
10452354
负责人：
Bingwei Lu
金额：
$ 23.61万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10452354
关键词：
Affect Apoptosis Behavior Behavioral Behavioral Symptoms Biochemical Bioenergetics Biological Process Biology Brain Brain Diseases Buffers Calcium Cells Cellular Structures Citric Acid Cycle Clinical Cognition Complex Defect Development Differentiation and Growth Disease Drosophila genus Electron Transport Emotions Enzymes Etiology FMR1 Face Fibroblasts Foundations Fragile X Syndrome Functional disorder Future Genetic Genetic Translation Goals Health Healthcare Homeostasis Human Hyperphagia Image Induced pluripotent stem cell derived neurons Inherited Intellectual functioning disability Investigation Knowledge Link Mediating Mental disorders Messenger RNA Metabolic Metabolism Mitochondria Modeling Molecular Neurobehavioral Manifestations Neurodegenerative Disorders Neurons Obesity Organelles Output Pathogenesis Pathogenicity Pathologic Patient Care Patients Pharmacology Physiological Positioning Attribute Process Production Proteins RNA RNA Binding RNA-Binding Proteins Regulation Role Seizures Signal Transduction Site Social Behavior Structure Symptoms Synapses Synaptic Transmission Synaptic plasticity Testing Translations Treatment Failure Voltage-Dependent Anion Channel autism spectrum disorder behavioral phenotyping dFMR1 gene effective therapy fly in vivo induced pluripotent stem cell mitochondrial dysfunction neural circuit neurophysiology neuropsychiatric disorder novel novel therapeutic intervention protein function protein protein interaction treatment effect treatment strategy uptake

项目摘要

Fragile X syndrome (FXS) is the most prevalent form of inherited intellectual disability and the primary genetic cause of autism. FXS is caused by loss of expression of the Fmr1 gene encoding Fragile X Mental Retardation Protein (FMRP), a protein with RNA-binding activity thought to act primarily as a translational regulator. In addition to intellectual disability, FXS patients present behavioral and cognitive symptoms, irregular physical features, and metabolic symptoms. The prevailing hypothesis of FXS pathogenesis posits FMRP as a promiscuous RNA-binding protein targeting hundreds of brain RNAs, with altered translation of these mRNA targets as the underlying cause of the synaptic and neural circuit defects and behavioral phenotypes seen in FXS. However, the recent clinical failures of treatment strategies targeting some of the key translational substrates of FMRP, and the current lack of effective treatment option for FXS, argue that investigations of new biological function of FMPR and new pathogenic mechanisms of FXS are warranted. Mitochondria are dynamic and complex organelles with essential roles in many aspects of biology, from energy production and intermediary metabolism to intracellular signaling and apoptosis. These broad functions position mitochondrion as a central player in human health. In neurons, mitochondria and synapses are intimately linked. In addition to their central role in bioenergetics, mitochondria are also critically important for maintaining cellular Ca2+ homeostasis. Ca2+ uptake by mitochondria helps buffer cytosolic Ca2+ transients arising from neuronal activation, protecting against the detrimental effects of Ca2+ influx. The ER-mitochondria contact site (ERMCS) are increasingly appreciated as key structures regulating mito-Ca2+ homeostasis, and there is an emerging role of altered ERMCS and mito-Ca2+ in the pathogenesis of neurodegenerative diseases. Whether ERMCS and its role in mito-Ca2+ homeostasis is affected in major neuropsychiatric diseases such as FXS is not known. The goal of this proposal is to test the central hypothesis that FMRP acts physically at ERMCS to direct Ca2+ signaling between organelles, and that defects in this process contribute to the etiology of FXS. To test this hypothesis, we propose to achieve the following Specific Aims in this exploratory project: Aim 1. Examine defects in ERMCS formation in the Drosophila dFmr1 model and FXS patient-derived models. Aim 2. Test the physiological roles of ERMCS proteins that direct mito-Ca2+ homeostasis in mediating FMRP function. By providing evidence for the involvement of ERMCS and mito-Ca2+ in mediating FMRP function at the organellar, synaptic, and organismal levels, these studies will lay the foundation for future mechanistic studies on the regulation and function of FMRP in normal synaptic and neuronal processes underlying brain function, cognition, emotion, and social behavior. Results from this study promise to significantly advance our understanding of the fundamental roles of mitochondria and Ca2+ signaling in FXS and various related mental disorders and offer novel and rational strategies to deliver health care for patients suffering from these devastating mental illnesses.

脆弱的X综合征（FXS）是遗传障碍的最普遍的形式和主要遗传自闭症的原因。 FXS是由编码脆弱X智力低下的FMR1基因表达的丧失引起的蛋白质（FMRP），一种具有RNA结合活性的蛋白质，主要充当转化调节剂。在在智力障碍中，FXS患者表现出行为和认知症状，身体不规则特征和代谢症状。 FXS发病机理的普遍假设将FMRP视为一个靶向数百个脑RNA的混杂RNA结合蛋白，这些mRNA的翻译改变了目标是突触和神经回路缺陷和行为表型的根本原因 FXS。但是，针对某些关键翻译的治疗策略的最新临床失败 FMRP的底物以及FXS目前缺乏有效的治疗选择，认为对新的调查必须掌握FMPR的生物学功能和FXS的新致病机制。线粒体是动态且复杂的细胞器，在生物学的许多方面具有重要作用，能源生产和中介代谢细胞内信号传导和凋亡。这些广泛的功能将线粒体定位为人类健康的中心参与者。在神经元中，线粒体和突触密切相关链接。除了其在生物能学中的核心作用外，线粒体对于维持至关重要细胞CA2+稳态。线粒体的Ca2+摄取有助于缓冲胞质Ca2+瞬变。神经元激活，防止Ca2+流入的有害作用。 ER-线粒体接触站点（ERMC）越来越多地被视为调节MITO-CA2+稳态的关键结构，并且有一个 ERMCS和MITO-CA2+改变的新兴作用在神经退行性疾病的发病机理中。无论 ERMC及其在MITO-CA2+稳态中的作用在主要神经精神疾病（例如FXS）中受到影响已知。该提案的目的是检验FMRP在ERMC上进行物理作用以指导的中心假设细胞器之间的Ca2+信号传导以及此过程中的缺陷有助于FX的病因。测试这个假设，我们建议在此探索性项目中实现以下特定目标：目标1。检查缺陷在果蝇DFMR1模型和FXS患者衍生模型中的ERMC形成中。目标2。测试 ERMCS蛋白的生理作用，该蛋白在介导FMRP功能中指导MITO-CA2+稳态。经过提供证据表明ERMC和MITO-CA2+参与细胞器中介导FMRP功能的证据，突触和生物水平，这些研究将为未来的机械研究奠定基础 FMRP在正常突触和神经元过程中的调节和功能，认知，认知，情感和社会行为。这项研究的结果有望大大提高我们对线粒体和CA2+信号在FXS和各种相关精神障碍中的基本作用，并提供为患有这些毁灭性精神疾病的患者提供医疗保健的新颖和理性策略。