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

• 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
• 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

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.

脆性X综合征（FXS）是遗传性智力残疾的最常见形式， 自闭症的原因FXS是由编码脆性X染色体智力低下的Fmr 1基因表达缺失引起的 蛋白（FMRP），一种具有RNA结合活性的蛋白，被认为主要作为翻译调节因子。在 除了智力残疾，FXS患者还表现出行为和认知症状，不规则的身体状况， 特征和代谢症状FXS发病机制的流行假说将FMRP假定为 一种混杂的RNA结合蛋白，靶向数百种脑RNA，改变了这些mRNA的翻译 靶点是突触和神经回路缺陷的根本原因， FXS。然而，最近针对一些关键的翻译的治疗策略的临床失败， FMRP的底物，以及目前缺乏FXS的有效治疗选择，认为新的研究 FMPR的生物学功能和FXS新的致病机制是必要的。 线粒体是一种动态的复杂细胞器，在生物学的许多方面都发挥着重要作用， 能量产生和中间代谢到细胞内信号传导和凋亡。这些广泛的功能 将安东定位为人类健康的核心参与者。在神经元中，线粒体和突触 有联系除了它们在生物能量学中的中心作用之外，线粒体对于维持细胞的存活也是至关重要的。 细胞内钙稳态。线粒体的Ca 2+摄取有助于缓冲细胞质Ca 2+瞬变， 神经元激活，防止Ca 2+内流的有害影响。ER-线粒体接触位点 （ERMCS）越来越多地被认为是调节线粒体-Ca 2+稳态的关键结构， ERMCS和线粒体Ca 2+改变在神经退行性疾病发病机制中的新作用。是否 ERMCS及其在线粒体-Ca 2+稳态中的作用在主要神经精神疾病如FXS中受到影响， 知道的该提案的目标是测试中心假设，即FMRP在ERMCS中物理作用， 细胞器之间的Ca 2+信号传导，在这个过程中的缺陷有助于FXS的病因。为了验证这一 假设，我们建议在这个探索性项目中实现以下具体目标：目标1。检查缺陷 在果蝇dFmr 1模型和FXS患者衍生模型中ERMCS的形成。目标2.测试 ERMCS蛋白在介导FMRP功能中指导线粒体-Ca 2+稳态的生理作用。通过 为ERMCS和mito-Ca 2+参与介导细胞器FMRP功能提供了证据， 突触和有机体水平，这些研究将为未来的机制研究奠定基础， FMRP在正常突触和神经元过程中的调节和功能是脑功能，认知， 情绪和社会行为。这项研究的结果有望大大提高我们对 线粒体和Ca 2+信号在FXS和各种相关精神障碍中的基本作用， 为患有这些毁灭性精神疾病的患者提供医疗保健的新颖而合理的战略。