Regulated Proteolysis and Long-Term Memory

调节蛋白水解和长期记忆

• 批准号: 7579973
• 负责人: ASHOK N HEGDE
• 金额: $ 26.65万
• 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/7579973
• 关键词: Alzheimer' s Disease; Aplysia; Biological Models; Blocking Antibodies; Brain Diseases; Cell Nucleus; Cells; Cyclic AMP-Responsive DNA-Binding Protein; Data; Drosophila genus; Excision; Gene Expression; Genetic Transcription; Goals; Impairment; Investigation; Lead; Learning; Light; Mammals; Marines; Mediating; Memory; Memory Loss; Motor; Motor Neurons; Names; Nervous System Physiology; Neurons; Neurotransmitters; Nuclear; Pathway interactions; Phosphorylation; Play; Presynaptic Terminals; Proteasome Inhibitor; Protein Biosynthesis; Protein Kinase C; Proteins; Proteolysis; Reflex action; Regulation; Regulation of Proteolysis; Research; Role; Sensory; Serotonin; Signal Transduction; Synapses; Synaptic plasticity; Testing; Time; Transcription Initiation; Translations; Ubiquitin; Ubiquitination; Vertebrates; behavioral sensitization; cell type; insight; long term memory; multicatalytic endopeptidase complex; neuronal cell body; presynaptic; protein degradation; research study

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（由申请人提供）： 项目摘要：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。用于研究突触可塑性的易于处理的模型系统是海兔感觉运动神经元突触的长期突触前促进，这是简单形式的学习和记忆的细胞机制。该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，以通过 cAMP 响应元件结合蛋白 (CREB) 激活基因转录。通常，CREB ​​的基因转录受到阻遏物的抑制。先前的研究表明，在海兔神经元中，CREB ​​抑制子 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，并表明磷酸化介导的 CREBIb 泛素化和降解调节对于诱导长期促进作用至关重要。在长期促进的诱导过程中，蛋白酶体的调节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显着不同。第二个目的是检验蛋白酶体在细胞核和突触末端受到差异调节的假设。这些研究可能有助于深入了解泛素蛋白酶体介导的蛋白水解作用的精确空间和时间调节有助于长期突触可塑性的机制。相关性：持续很长时间的记忆只有在强烈或反复的感官刺激下才能形成。在形成持久记忆之前，需要降解抑制记忆形成的关键蛋白质。抑制蛋白通过附着一个称为泛素的标签来标记降解，并被细胞中称为蛋白酶体的部分降解。在许多脑部疾病（如阿尔茨海默病）中，蛋白质降解是异常的。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。