Regulated Proteolysis and Long-Term Memory

描述（由申请人提供）：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易处理的模型系统是在失智症中感觉-运动神经元突触的长期突触前易化，这是一种简单形式的学习和记忆的细胞机制。这项提案的总体目标是调查如何泛素-蛋白酶体途径有助于长期促进。长期易化需要从神经递质5-HT到细胞核的信号转导，以通过cAMP反应元件结合蛋白（CREB）激活基因转录。通常，CREB的基因转录被阻遏物抑制。先前的研究表明，在失智症神经元中，CREB阻遏物CREBIb通过泛素-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泛素化和降解的调节对于诱导长期易化至关重要。在诱导长时程易化过程中，蛋白酶体的调节也可能发挥关键作用。初步数据表明，突触末梢中的蛋白酶体活性与核中的蛋白酶体活性显著不同。第二个目的是检验蛋白酶体在细胞核和突触末梢中受到差异调节的假设。这些研究很可能提供深入了解的机制，通过精确的空间和时间调节的泛素-蛋白酶体介导的蛋白水解有助于长期突触可塑性。相关性：只有在强烈或反复刺激感官的情况下，记忆才能持续很长一段时间。一种抑制记忆形成的关键蛋白质需要在持久记忆形成之前被降解。抑制蛋白通过附着一种称为泛素的标签而被标记为降解，并被称为蛋白酶体的细胞部分降解。蛋白质降解在许多脑部疾病中是不正常的，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以及脑部疾病。

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.