Regulation of Memory by the microRNA/RISC Pathway

描述（由申请人提供）：神经科学剩下的谜团之一是记忆是如何储存几天，几周或几年的。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共同的记忆特征。定位于突触的蛋白质合成特别令人感兴趣，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，蛋白质合成如何在神经系统中进行部署，并有助于形成特定的记忆，目前还不清楚。我们已经使用荧光报告构建可视化突触蛋白质的合成在果蝇，形成长期记忆。气味与电击的关联与显示突触特异性特征的局部蛋白质合成以及mRNA运输到突触区域的诱导相关。记忆的这些特征似乎是由RNA诱导沉默复合物（RISC）控制的，该复合物位于一条涉及蛋白酶体对RISC调节的途径中。RISC的组成部分，阿米蒂奇，被发现是泛素化和蛋白酶体依赖性的方式降解，显然有助于从RISC抑制释放突触蛋白合成。这些观察结果提出了一些重要的问题，以了解记忆的机制。我们能否建立一个细粒度的神经地图，以显示特定记忆形成时蛋白质合成发生的位置？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？它们与突触在新的稳定状态下的维持有什么关系？我们刚刚开始了解RISC通路在突触中的作用和生物化学，但作为这些事件的明显调节器，我们相信这种理解将阐明记忆背后的生物化学和细胞机制。这项研究的强大潜力，使临床贡献不应被忽视，因为它是显而易见的，这些机制在哺乳动物和人类的突触。这项研究可能会确定新的治疗目标，以帮助患有记忆障碍（例如，阿尔茨海默病）和突触活动（例如，癫痫）的患者。公共卫生相关性：神经系统的许多病理和一些发育障碍与记忆的形成、维持或回忆的缺陷有关。即使在记忆的生化机制不是主要缺陷的情况下，增强或恢复记忆的治疗工具也会为患者提供相当大的益处，并减轻这种疾病对社会的成本和负担。在这项建议中所描述的工作是直接针对一个新的机制的表征潜在的记忆。新的生物化学途径的记忆基础的描述提供了深入的设计和治疗药物的目标。该项目提供了相当大的潜力，通过最终开发新的治疗药物，使记忆缺陷患者受益。

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.