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Regulation of Memory by the microRNA/RISC Pathway

microRNA/RISC 通路对记忆的调节

基本信息

批准号：
8197612
负责人：
Samuel M Kunes
金额：
$ 40.6万
依托单位：
HARVARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-01-01 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8197612
关键词：
Acute Address Adult Afferent Neurons Alzheimer&apos s Disease Biochemical Biochemical Pathway Biochemistry Biogenesis Brain Cells Cereals Characteristics Clinical Defect Development Disease Drosophila genus Epilepsy Event Functional disorder Human In Situ Hybridization Invertebrates Left Maintenance Maps Mediating Memory Memory Disorders Messenger RNA MicroRNAs Modification Molecular Nervous system structure Neurons Neurosciences Odors Pathway interactions Patients Protein Biosynthesis Proteins RNA-Induced Silencing Complex Regulation Reporter Role Sensory Shock Societies Specificity Structure Synapses Synaptic plasticity Therapeutic Therapeutic Agents Time Transcript Vertebrates Work calmodulin-dependent protein kinase II conditioning cost design developmental disease experience insight interest long term memory memory recall multicatalytic endopeptidase complex neural circuit new therapeutic target novel novel therapeutics promoter relating to nervous system tool transgene expression

项目摘要

PROJECT SUMMARY/ABSTRACT One of the remaining mysteries of neuroscience is how memories are stored for periods of days, weeks or years. It has been known for some time that the formation of stable memory requires protein synthesis, a feature of memory common to vertebrates and invertebrates. Protein synthesis localized to the synapse is of special interest because it might confer selective synaptic change and the stable modification of a neural circuit. But how protein synthesis is deployed across the nervous system and contributes to the formation of a particular memory is unclear. We have used fluorescent reporter constructs to visualize synaptic protein synthesis in Drosophila that form a long-term memory. The association of an odor with electric shock was correlated with local protein synthesis that displayed features of synaptic specificity, and the induction of mRNA transport to synaptic regions. These features of memory appeared to be controlled by the RNA- Induced Silencing Complex (RISC) in a pathway involving RISC regulation by the Proteasome. A RISC component, Armitage, was found to be ubiquitinated and degraded in a Proteasome-dependent fashion, evidently contributing to the release of synaptic protein synthesis from RISC suppression. These observations raise a number of questions of importance to understanding the mechanisms underlying memory. Can we build a fine-grained neural map of where protein synthesis occurs as a particular memory forms? Can we build a map of where the regulation of protein synthesis is required? What are the temporal characteristics of synaptic protein synthesis and how are they related to the maintenance of a synapse in a stable new state? We have only begun to understand the role and biochemistry of the RISC pathway at the synapse, but as an evident regulator of these events, we believe this understanding will illuminate the biochemical and cellular mechanisms underlying memory. The strong potential of this study to make clinical contributions should not be overlooked, as it is evident that these mechanisms operate at mammalian and human synapses. This study will likely identify new targets for therapeutic efforts to aid patients with disorders of memory (for example, Alzheimer's Disease) and synaptic activity (for example, epilepsy).

项目总结/摘要神经科学剩下的谜团之一是记忆如何储存数天、数周或数周的时间年一段时间以来，人们已经知道，稳定记忆的形成需要蛋白质合成，脊椎动物和无脊椎动物共有的记忆特征。位于突触的蛋白质合成特别感兴趣的是，因为它可能赋予选择性突触变化和神经元的稳定修饰。电路.但是蛋白质合成如何在神经系统中部署并有助于形成特定的记忆是不清楚的。我们已经使用荧光报告构建可视化突触蛋白果蝇中形成长期记忆的合成。气味与电击的联系是与显示突触特异性特征的局部蛋白质合成相关， mRNA转运到突触区域。这些记忆的特征似乎是由RNA控制的- 诱导沉默复合物（RISC）在涉及蛋白酶体调控RISC的途径中。一个RISC 发现Armitage以蛋白酶体依赖的方式被泛素化和降解，这显然有助于从RISC抑制中释放突触蛋白合成。这些观察结果提出了一些重要的问题，以了解机制潜在的记忆我们能否建立一个细粒度的神经地图，特定的记忆形式我们能否建立一个蛋白质合成调控所需的地图？突触蛋白质合成的时间特征是什么？它们与突触蛋白质合成的时间特征有什么关系？维持突触在一个稳定的新状态我们才刚刚开始了解它的作用，突触RISC通路的生物化学，但作为这些事件的明显调节剂，我们相信，这种理解将阐明记忆的生化和细胞机制。坚强这项研究做出临床贡献的潜力不应被忽视，因为很明显，机制在哺乳动物和人类的突触中起作用。这项研究可能会确定新的目标，帮助患有记忆障碍（例如，阿尔茨海默病）和突触神经元障碍的患者的治疗努力。活动（例如癫痫）。