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mRNA transport and local translation of actin-binding proteins in the Fragile X Syndrome

脆性 X 综合征中肌动蛋白结合蛋白的 mRNA 转运和局部翻译

基本信息

批准号：
325255501
负责人：
Professor Dr. Martin Korte
金额：
--
依托单位：
Abteilung Zelluläre Neurobiologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2016
资助国家：
德国
起止时间：
2015-12-31 至 2020-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/325255501?language=en
关键词：
mRNA transport local translation actin

项目摘要

Fragile X Syndrome (FXS) is the most common known monogenetic cause for autism. This genetically caused neuropsychiatric disorder is of high relevance in order to shed light on the importance of a balanced synaptogenesis and fine-tuning of neuronal. The most noticeable phenotype of FXS in the CNS is an apparent excess of immature dendritic spines, tiny protrusions on dendrites which represent the postsynaptic structures on the majority of neurons in the cortex. As knowledge about these structures increases, it becomes obvious that even subtle changes in synaptic function or development of spine morphology can result in severe cognitive abnormalities for a lifetime. This indicates that a deeper understanding of the molecular pathways involved in these disorders could not only provide us with potential cures but would eventually help to better understand the formation, function, and ever changing structure of synapses in the healthy central nervous system. FXS is characterized by the absence of the FMRP protein which binds mRNAs and indeed the altered spine density and morphology phenotype can be linked to a direct role of FMRP in activity-dependent mRNA transport, docking and local translation. In fact, translational dysregulation has recently been suggested to be a major factor in causing autism. Taken this into account, in our current project proposal we would like to use FXS as a model system to unravel crucial mechanisms of local dendritic protein synthesis and the specific function in synapse formation and maturation in the murine hippocampus in order to prepare the ground for translational applications. As the development, plasticity and maintenance of spine structure - whose impairment represents a hallmark of the FXS syndrome - is tightly linked to the actin cytoskeleton it is of high interest whether indeed one of the key features disturbed in FXS might be the crucial role of FMRP in regulating the transport and local translation of actin-binding proteins (ABPs). And indeed one of the most prominent features of FXS is the apparent spine morphology phenotype. Using different approaches like fluorescence in-situ hybridization and tools to visualize both mRNA transport and local protein synthesis we will be able to detect alterations in the localization of ABPs mRNAs in the course of FXS starting with earliest time points of synaptogenesis up to the mature state and correlate these changes to the spine phenotypes observed. These experiments will shed light on the role of locally translated APBs in synapse development and function in the healthy CNS as not much is known here either. As the experiments will be performed under basal conditions as well as upon induction of activity patterns known to reflect cellular processes crucial for learning and memory formation, we will therefore be able to contribute to a better and deeper understanding of the hallmark of FXS, a knowledge which is a pre-requisite for a rational treatment approach.

脆性X综合征(FXS)是自闭症最常见的单基因致病因素。这种遗传导致的神经精神障碍具有很高的相关性，以阐明平衡的突触发生和神经元微调的重要性。中枢神经系统中最明显的FXS表型是明显的未成熟树突棘过多，树突上的微小突起代表了大脑皮层大多数神经元上的突触后结构。随着对这些结构的了解的增加，很明显，即使是突触功能的细微变化或脊柱形态的发展也可能导致终身严重的认知异常。这表明，深入了解这些疾病所涉及的分子途径不仅可以为我们提供潜在的治疗方法，而且最终将有助于更好地了解健康中枢神经系统中突触的形成、功能和不断变化的结构。FXS的特点是缺乏与mRNAs结合的FMRP蛋白，确实，脊柱密度和形态的改变可能与FMRP在活性依赖的mRNA运输、对接和局部翻译中的直接作用有关。事实上，翻译失调最近被认为是导致自闭症的一个主要因素。考虑到这一点，在我们目前的项目提案中，我们希望使用FXS作为一个模型系统来揭示局部树突状蛋白合成的关键机制以及小鼠海马区突触形成和成熟的特定功能，为翻译应用奠定基础。由于脊柱结构的发育、可塑性和维持-其损伤是FXS综合征的标志-与肌动蛋白细胞骨架密切相关，FXS的关键特征之一是否确实是FMRP在调节肌动蛋白结合蛋白(ABPs)的运输和局部翻译中的关键作用引起了高度关注。事实上，FXS最显著的特征之一就是明显的脊椎形态表型。使用不同的方法，如荧光原位杂交和工具来可视化mRNA运输和局部蛋白质合成，我们将能够检测在FXS过程中ABPs mRNAs定位的变化，从突触发生的最早时间点到成熟状态，并将这些变化与观察到的脊柱表型相关联。这些实验将阐明局部翻译的APB在健康中枢神经系统突触发育和功能中的作用，因为这里也知道得很少。由于实验将在基础条件下进行，并在诱导已知的反映学习和记忆形成关键的细胞过程的活动模式时进行，因此我们将能够更好和更深入地理解FXS的标志，这是合理治疗方法的先决条件。