Regulated Proteolysis and Long-Term Memory

调节蛋白水解和长期记忆

• 批准号: 7050683
• 负责人: ASHOK N HEGDE
• 金额: $ 29.57万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7050683
• 关键词: biological signal transduction; cAMP response element binding protein; cell nucleus; electrophysiology; immunocytochemistry; laboratory mouse; long term memory; neural plasticity; phosphorylation; proteasome; protein degradation; proteolysis; synapses; ubiquitin

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.

描述(申请人提供)：项目摘要：阐明突触可塑性的潜在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容易处理的模型系统是海藻中感觉到运动神经元突触的长期突触前促进，这是一种简单形式学习和记忆的细胞机制。这项建议的总体目标是调查泛素-蛋白酶体途径如何有助于长期促进。长期的易化需要从神经递质5-羟色胺到核内的信号转导，以通过cAMP反应元件结合蛋白(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。以往的研究表明，在海兔神经元中，CREB抑制物CREBIb被泛素-蛋白酶体途径降解。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，并证明磷酸化介导的CREBIb泛素化和降解的调节是诱导长期促进的关键。在诱导长期易化的过程中，蛋白酶体的调节也可能起到关键作用。初步数据显示，突触末梢的蛋白酶体活性与核内的蛋白酶体活性明显不同。第二个目的是验证蛋白酶体在细胞核和突触终末受到不同调控的假设。这些研究可能对泛素-蛋白酶体介导的蛋白分解的精确空间和时间调节有助于长期突触可塑性的机制提供洞察力。相关性：持续很长时间的记忆只有在强烈或反复刺激感官的情况下才会形成。一种抑制记忆形成的关键蛋白质需要在形成持久记忆之前被降解。抑制蛋白通过附着一种名为泛素的标签来标记为降解，并被细胞中名为蛋白酶体的部分降解。蛋白质降解在阿尔茨海默氏症等许多大脑疾病中都是异常的。这项研究可能会揭示蛋白质降解障碍如何导致记忆丧失以及大脑疾病。