Molecular and cellular mechanisms that underlie synaptic maturation

突触成熟的分子和细胞机制

• 批准号: 10266761
• 负责人: Timothy J. Mosca
• 金额: $ 32.66万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10266761
• 关键词: Address; Affect; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Biochemistry; Biological; Cells; Communication; Complex; Confocal Microscopy; Data; Defect; Development; Disease; Drosophila genus; Endocytosis; Ensure; Epilepsy; Etiology; Event; Failure; Foundations; Genes; Genetic; Genetic Transcription; Goals; Growth; Health; Human; Impairment; Integral Membrane Protein; Intellectual functioning disability; Invertebrates; Learning; Ligands; Ligation; Mediating; Molecular; Molecular Genetics; Morphology; Muscle; Mutation; Nervous System Physiology; Nervous system structure; Neurobiology; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neuromuscular Junction; Neuronal Differentiation; Neurons; Nuclear; Nuclear Import; Pathway interactions; Peptide Hydrolases; Phenocopy; Presenile Alzheimer Dementia; Presynaptic Receptors; Presynaptic Terminals; Process; Proteins; RNA interference screen; Reagent; Resolution; Role; Schizophrenia; Side; Signal Pathway; Signal Transduction; Site; Stereotyping; Structure; Synapses; Synaptic Transmission; Synaptic plasticity; Tissues; Vertebrates; WNT Signaling Pathway; Western Blotting; Work; autism spectrum disorder; cell type; density; experimental study; gamma secretase; gene function; high resolution imaging; in vivo; insight; knock-down; loss of function; mutant; nervous system disorder; neuron development; neurotransmitter release; nicastrin protein; postsynaptic; presenilin; presynaptic; receptor; recruit; response; tool; trafficking; transmission process

In all nervous systems, from invertebrates to humans, newly formed synaptic connections are not yet optimally functional. All synapses must undergo a process of synaptic maturation to transition from structurally simple and functionally unrefined connections to structurally complex connections capable of robust synaptic transmission and plasticity. This process is critically important, as failures in synaptic maturation have a marked bearing in health and disease, underlying neurodevelopmental disorders like autism and epilepsy and intellectual disabilities like schizophrenia. Recent work has even suggested that the maturation process may also be hijacked in neurodegenerative diseases like Alzheimer’s. Despite this importance, the molecular mechanisms that underlie synaptic maturation remain poorly understood. Structural events including the recruitment of postsynaptic proteins to nascent presynaptic terminals must preface functional maturation, but even our understanding of the genes and pathways that enable these events remains incomplete. Specifically, the presynaptic receptors involved in maturation remain woefully understudied and there are still critical gaps in our understanding of how established maturation signals are processed postsynaptically to promote development. The long-term goal of this proposal is to identify the molecules that ensure normal synaptic maturation and determine the mechanisms by which they function. To understand these fundamental events, we will use a combination of genetics, high-resolution imaging, and biochemistry approaches to investigate the mechanisms that underlie synaptic maturation. Our preliminary work has identified three transmembrane proteins that likely function in structural synaptic maturation. Mutations in these genes have been associated with early-onset Alzheimer’s disease, failures in neuronal differentiation, and amyotrophic lateral sclerosis, underscoring their importance in a normally functioning nervous system. We will first characterize how each of these molecules contributes to synaptic growth and maturation. Following, we will determine where these genes are expressed and whether they function presynaptically or postsynaptically to mediate synaptic maturation. Finally, we will begin to determine the mechanism by which these genes function and intersect with established signaling pathways that regulate synaptic maturation and development. We expect that this work will first identify new genes that function pre- and postsynaptically to ensure synaptic maturation and second, the mechanisms by which they achieve this goal. With a deeper understanding of the normal function of these genes, we can better understand how they work to stave off disorders like Alzheimer’s disease when present and how mutations in those genes can contribute to the progression of neurodegenerative diseases. In so doing, we will establish a fundamental foundation for the cellular events underlying maturation and begin to inform how impaired synaptic maturation can underlie neurodevelopmental disorders, intellectual disabilities, and neurodegenerative diseases.

在所有神经系统中，从无脊椎动物到人类，新形成的合成连接尚无最佳功能。所有突触必须在合成成熟的过程中，从结构简单且功能未精制的连接过渡到能够稳健合成传播和可塑性的结构复杂连接。这个过程至关重要，因为合成成熟的失败对健康和疾病具有明显的影响，其基本的神经发育疾病（如自闭症，癫痫和癫痫和精神分裂症）等智力残疾。最近的工作甚至表明，成熟过程也可能会被劫持在阿尔茨海默氏症等神经退行性疾病中。尽管这一重要性，但基础突触成熟的分子机制仍然很少理解。结构事件包括将突触后蛋白募集到新生的突触前末端，必须前言功能问题，但即使我们对使这些事件的基因和途径的理解仍然不完整。具体而言，涉及成熟的突触前受体仍然充分理解，并且我们对建立成熟信号的理解仍然存在关键的差距，以促进发展以促进发展。该提案的长期目标是确定确保正常突触成熟的分子并确定其发挥作用的机制。为了了解这些基本事件，我们将使用仿制药，高分辨率成像和生物化学方法的组合来研究突触成熟的基础的机制。我们的初步工作已经确定了三种可能在结构合成成熟中起作用的跨膜蛋白。这些基因的突变与早期发作的阿尔茨海默氏病，神经元分化的失败和肌萎缩性侧索硬化症有关，强调了它们在正常功能正常的神经系统中的重要性。我们将首先表征这些分子中的每个分子如何促进突触生长和成熟。随后，我们将确定这些基因的表达位置，以及它们是突触前还是在突触后中位数合成成熟。最后，我们将开始确定这些基因与调节突触成熟和发育的已建立信号通路相交的机制。我们预计这项工作将首先识别出伴有前后功能的新基因，以确保突触成熟，其次，其实现这一目标的机制。有了更深入的了解这些基因的正常功能，我们可以更好地理解它们如何在存在时如何保持诸如阿尔茨海默氏病等疾病，以及这些基因中的突变如何有助于神经退行性疾病的发展。通过这样做，我们将为成熟基础的细胞事件建立一个基本基础，并开始告知合成成熟受损如何在神经发育障碍，智力障碍和神经退行性疾病的基础下如何构成基础。