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

脆性X综合征(FXS)是遗传性智能障碍最常见的形式，也是主要的遗传缺陷 自闭症的原因。FXS是由编码脆性X智力低下的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，被认为主要作为翻译调节因子。在……里面 除智力残疾外，FXS患者还会出现行为和认知症状，身体不规则 特征和代谢症状。FXS发病机制的流行假说认为FMRP是一种 以数百个脑RNA为靶标的混杂RNA结合蛋白，这些RNA的翻译发生了变化 靶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，最近临床上针对一些关键的翻译策略的治疗策略失败 FMRP的底物，以及目前缺乏有效的FXS治疗选择，认为对新的 FMPR的生物学功能和FXS的新致病机制是必要的。 线粒体是动态而复杂的细胞器，在生物学的许多方面都扮演着重要的角色，从 能量的产生和细胞内信号和细胞凋亡的中间代谢。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。除了在生物能量学中的核心作用外，线粒体对维持 细胞内钙动态平衡。线粒体对Ca~(2+)的摄取有助于缓冲由线粒体引起的胞浆钙瞬变 神经元激活，保护免受钙离子内流的不利影响。内质网-线粒体接触部位 (ERMCs)作为调节线粒体-钙稳态的关键结构越来越受到重视，而且有一种 改变的ERMCS和丝裂原钙离子在神经退行性疾病发病机制中的新作用。是否 在FXS等主要神经精神疾病中，ERMCS及其在丝裂原-钙稳态中的作用受到影响 为人所知。这项提议的目标是检验中心假设，即FMRP在ERMCS实际行动，以指导 细胞器之间的钙信号转导，这一过程中的缺陷导致了FXS的病因学。为了测试这一点 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dFmr1模型和FXS患者衍生模型中ERMCS的形成。目标2.测试 指导线粒体-钙稳态的ERMCS蛋白在介导FMRP功能中的生理作用。通过 为ERMCS和MITO-Ca~(2+)参与调节细胞器FMRP功能提供了证据。 这些研究将为未来关于突触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作用 情感和社会行为。这项研究的结果有望极大地促进我们对 线粒体和钙信号在FXS和各种相关精神障碍中的基础作用 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。

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.