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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.

脆性 X 综合征 (FXS) 是遗传性智力障碍最常见的形式，也是主要的遗传性疾病自闭症的原因。 FXS 是由编码脆性 X 型智力迟钝的 Fmr1 基因表达缺失引起的蛋白质 (FMRP)，一种具有 RNA 结合活性的蛋白质，被认为主要充当翻译调节因子。在除了智力障碍外，FXS 患者还表现出行为和认知症状、身体不规律特征和代谢症状。 FXS 发病机制的流行假说认为 FMRP 是一种混杂的 RNA 结合蛋白靶向数百个大脑 RNA，这些 mRNA 的翻译发生了改变目标作为突触和神经回路缺陷以及行为表型的根本原因 FXS。然而，最近针对一些关键转化的治疗策略在临床上失败了。 FMRP 的底物以及目前缺乏有效的 FXS 治疗方案，认为新的研究 FMPR 的生物学功能和 FXS 的新致病机制是有根据的。线粒体是动态且复杂的细胞器，在生物学的许多方面发挥着重要作用，从能量产生和中间代谢到细胞内信号传导和细胞凋亡。这些广泛的功能将线粒体定位为人类健康的核心角色。在神经元中，线粒体和突触密切相关已链接。除了在生物能学中的核心作用外，线粒体对于维持细胞 Ca2+ 稳态。线粒体对 Ca2+ 的吸收有助于缓冲由线粒体引起的胞质 Ca2+ 瞬变神经元激活，防止 Ca2+ 流入的有害影响。 ER-线粒体接触位点（ERMCS）作为调节线粒体钙稳态的关键结构越来越受到重视，并且有一个改变的 EMCS 和 mito-Ca2+ 在神经退行性疾病发病机制中的新作用。无论 EMCS 及其在线粒体 Ca2+ 稳态中的作用在主要神经精神疾病（如 FXS）中不受影响已知。该提案的目标是测试中心假设，即 FMRP 在 EMCS 上物理作用以指导细胞器之间的 Ca2+ 信号传导以及该过程中的缺陷导致了 FXS 的病因学。为了测试这个假设，我们建议在这个探索性项目中实现以下具体目标：目标 1. 检查缺陷果蝇 dFmr1 模型和 FXS 患者衍生模型中的 EMCS 形成。目标 2. 测试 EMCS 蛋白在介导 FMRP 功能中指导线粒体 Ca2+ 稳态的生理作用。经过为 EMCS 和 mito-Ca2+ 参与介导细胞器 FMRP 功能提供证据，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 在大脑功能、认知、正常突触和神经元过程中的调节和功能情绪和社会行为。这项研究的结果有望显着增进我们对线粒体和 Ca2+ 信号传导在 FXS 和各种相关精神障碍中的基本作用并提供新颖而合理的策略为患有这些毁灭性精神疾病的患者提供医疗保健。