Regulation of Memory by the microRNA/RISC Pathway

microRNA/RISC 通路对记忆的调节

• 批准号: 7995161
• 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
• 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/7995161
• 关键词: Acute; Address; Adult; Afferent Neurons; Alzheimer' s Disease; Biochemical; Biochemical Pathway; Biochemistry; Biogenesis; Brain; Cells; Cereals; Characteristics; Clinical; Defect; Development; Disease; Drosophila genus; Epilepsy; Event; Functional disorder; Health; 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

DESCRIPTION (provided by applicant): 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). PUBLIC HEALTH RELEVANCE: Many pathological and some developmental disorders of the nervous system are associated with defects in the formation, maintenance or recall of memories. Even where the biochemical mechanisms underlying memory are not the primary defect, therapeutic tools to enhance or restore memory would offer considerable benefit to the patient and alleviate the cost and burden of such disorders to society. The work described in this proposal is aimed directly at the characterization of a novel mechanism underlying memory. The description of new biochemical pathways underlying memory offers insights into the design and targeting of therapeutic agents. This project offers considerable potential to benefit patients with memory deficiencies via the eventual development of novel therapeutic agents.

描述（由申请人提供）：神经科学的其余奥秘之一是如何存储在几天，几周或几年的时期。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，这是脊椎动物和无脊椎动物常见的记忆特征。定位于突触的蛋白质合成具有特殊的兴趣，因为它可能赋予选择性突触变化和神经回路的稳定修饰。但是，如何在神经系统中部署蛋白质合成并有助于特定记忆的形成。我们已经使用荧光记者构建体来可视化果蝇中的突触蛋白合成，形成了长期记忆。气味与电击的关联与局部蛋白质的合成相关，该蛋白质的合成表现出突触特异性的特征，以及将mRNA转运诱导到突触区域的诱导。这些记忆的这些特征似乎是由RNA诱导的沉默复合物（RISC）控制的，该途径涉及蛋白酶体的RISC调节。发现RISC成分Armitage被发现以蛋白酶体依赖性的方式被泛素化并降解，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许多重要的问题，以了解记忆的基本机制。我们可以建立一个细粒神经图，以作为特定记忆形式出现蛋白质合成的位置吗？我们可以构建一张图的地图，说明需要蛋白质合成的调节吗？突触蛋白合成的时间特征是什么，它们与稳定的新状态下的突触保持如何关系？我们才开始理解RISC途径在突触中的作用和生物化学，但​​是作为这些事件的明显调节者，我们相信这种理解将阐明记忆的生化和细胞机制。这项研究的强大潜力不应忽略临床贡献，因为很明显，这些机制在哺乳动物和人类突触中起作用。这项研究可能会确定用于帮助记忆障碍患者（例如，阿尔茨海默氏病）和突触活动（例如，癫痫）的新目标。公共卫生相关性：神经系统的许多病理和某些发育障碍与记忆的形成，维护或回忆中的缺陷有关。即使记忆的生化机制不是主要缺陷，增强或恢复记忆的治疗工具也会为患者带来可观的好处，并减轻此类疾病的成本和负担。该提案中描述的工作直接针对一种新型机制的表征。对新生物化学途径的描述提供了对治疗剂的设计和靶向的见解。该项目提供了巨大的潜力，可通过最终开发新型治疗剂来使记忆缺陷的患者受益。