Regulated Proteolysis and Long-Term Memory

项目概述：阐明突触可塑性的机制可能有助于理解神经系统的正常和异常功能。研究突触可塑性的一个可处理的模型系统是长时间的突触前促进的感觉-运动神经元突触，这是一种简单的学习和记忆形式的细胞机制。本提案的总体目标是研究泛素-蛋白酶体途径如何促进长期促进。长期促进需要从神经递质5-HT到细胞核的信号转导，通过camp响应元件结合蛋白（CREB）激活基因转录。正常情况下，CREB的基因转录受到抑制因子的抑制。先前的研究表明，在泛素-蛋白酶体途径下，泛素-蛋白酶体可降解CREB抑制因子CREBIb。初步结果表明，CREBIb被蛋白激酶c磷酸化。第一个目的是研究磷酸化对CREBIb泛素化的调节，并表明磷酸化介导的CREBIb泛素化和降解的调节对于诱导长期促进至关重要。在诱导长期促进过程中，蛋白酶体的调控也可能发挥关键作用。初步数据表明，突触末端的蛋白酶体活性与细胞核中的蛋白酶体活性有显著差异。第二个目的是验证蛋白酶体在细胞核和突触末端受到不同调节的假设。这些研究可能为泛素-蛋白酶体介导的蛋白质水解的精确时空调节有助于长期突触可塑性的机制提供见解。关联性：长时间的记忆只有在强烈的或反复的感官刺激下才能形成。在形成持久记忆之前，一种抑制记忆形成的关键蛋白质需要被降解。抑制蛋白通过附着一个称为泛素的标签来标记降解，并被称为蛋白酶体的细胞部分降解。这种蛋白质降解在许多脑部疾病中都是不正常的，比如阿尔茨海默氏症。这项研究可以揭示蛋白质降解受损如何导致记忆丧失和脑部疾病。

DESCRIPTION (provided by applicant): Project Summary: Elucidation of mechanisms underlying synaptic plasticity is likely to aid in understanding both normal and abnormal functions of the nervous system. A tractable model system for investigating synaptic plasticity is long-term presynaptic facilitation of sensory-to-motor neuron synapses in Aplysia, the cellular mechanism underlying a simple form of learning and memory. The overall goal of this proposal is to investigate how the ubiquitin-proteasome pathway contributes to long-term facilitation. Long-term facilitation requires signal transduction from the neurotransmitter 5-HT to the nucleus for activation of gene transcription by the cAMP-responsive element binding protein (CREB). Normally, gene transcription by CREB is inhibited by repressers. Previous studies revealed that in Aplysia neurons, the CREB represser CREBIb is degraded by the ubiquitin-proteasome pathway. Preliminary results indicate that CREBIb is phosphorylated by protein kinase C. The first aim is to investigate regulation of CREBIb ubiquitination by phosphorylation and to show that phosphorylation-mediated regulation of CREBIb ubiquitination and degradation is critical for induction of long-term facilitation. During induction of long-term facilitation, regulation of proteasome is likely to play a critical role as well. Preliminary data show that the proteasome activity in the synaptic terminals significantly differs from the proteasome activity in the nucleus. The second aim is to test the hypothesis that the proteasome is differentially regulated in the nucleus and in the synaptic terminals. These studies are likely to provide insights into the mechanisms by which precise spatial and temporal regulation of ubiquitin-proteasome-mediated proteolysis contribute to long-term synaptic plasticity. Relevance: Memory that lasts a long-period of time forms only with strong or repeated stimulation of the senses. A key protein that suppresses memory formation needs to be degraded before long-lasting memory can form. The suppressor protein is marked for degradation by attachment of a tag called ubiquitin and is degraded by a part of the cell named the proteasome. The protein degradation is abnormal in many brain diseases like Alzheimer's. This research could shed light on how impairment in protein degradation could lead to memory loss as well as brain diseases.