Molecular and cellular mechanisms that underlie synaptic maturation

突触成熟的分子和细胞机制

• 批准号: 10471952
• 负责人: Timothy J. Mosca
• 金额: $ 34.13万
• 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/10471952
• 关键词: Address; Affect; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Biochemistry; Biological; Cells; Communication; Complex; Confocal Microscopy; Data; Defect; Development; Disease; Drosophila genus; Early Onset Alzheimer Disease; 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; Presynaptic Receptors; Presynaptic Terminals; Process; Proteins; RNA interference screen; Reagent; Resolution; Role; Schizophrenia; Side; Signal Pathway; Signal Transduction; Site; Stereotyping; 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，新形成的突触连接尚未达到最佳功能。诸如精神分裂症之类的智力也被劫持在神经退行性疾病中，例如阿尔茨海默氏症，涉及的突触者仍然严重研究，我们的理解中仍然存在关键的差距突触的蛋白质可能在结构的成熟度中发挥作用。为了介导突触成熟。有了更深入的了解，我们可以更好地理解诸如阿尔茨海默氏病沃恩（Wohen）等疾病中的疾病和这些基因中的哇突变，从而有助于神经退行性疾病。神经发育障碍，智力疾病和神经退行性疾病的基础突触成熟如何受损。