Ubiquitination as an acute regulator of synaptic transmission

泛素化作为突触传递的急性调节因子

• 批准号: 8174415
• 负责人: FELIX E SCHWEIZER
• 金额: $ 23.1万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8174415
• 关键词: Action Potentials; Acute; Affect; Alzheimer' s Disease; Applications Grants; Basic Science; Calcium; Cell physiology; Clinical; Data; Development; Disease; Event; Excitatory Postsynaptic Potentials; Frequencies; Functional disorder; Future; Half-Life; Health; Homeostasis; Hour; Huntington Disease; Impairment; Individual; Link; Mediating; Molecular; Mono-S; Mutation; Nervous System Physiology; Nervous system structure; Neurodegenerative Disorders; Neurons; Neurotransmitters; Parkinson Disease; Pathway interactions; Pesticides; Physiological; Play; Post-Translational Protein Processing; Presynaptic Terminals; Probability; Process; Proteasome Inhibition; Protein Dynamics; Protein Inhibition; Proteins; Proteomics; Regulation; Regulatory Pathway; Role; Shapes; Signal Transduction; Signaling Protein; Staging; Symptoms; Synapses; Synaptic Transmission; System; Testing; Time; Toxic Environmental Substances; Ubiquitin; Ubiquitination; Vesicle; Work; d(CH2)5(Tyr(Me)(2))AVP; design; insight; interest; multicatalytic endopeptidase complex; nervous system disorder; neurotransmitter release; novel; postsynaptic; presynaptic; protein degradation; protein misfolding; research study; response; synaptic function; synaptic inhibition; synaptogenesis

DESCRIPTION (provided by applicant): Synaptic transmission is a critical feature of the nervous system and is as such tightly regulated on many different time-scales. The ubiquitin-proteasome system (UPS) plays an important role in synaptic transmission by maintaining appropriate protein homeostasis. The UPS regulates synapse formation during development, by shaping long-term plasticity, by altering the number of active synapses and by changing the size of vesicle pools. All of these regulatory functions occur on a time scale of hours to days and are consistent with the central role of the UPS in protein degradation: covalent attachment of ubiquitin tags proteins for degradation by the proteasome. We have recently discovered that the UPS also regulates neurotransmitter release on a time-scale of a few minutes or less. This led us to the hypothesis that ubiquitination at the synapse rapidly regulates release by changing the activity level of target proteins rather than changing their half-life. Thus, protein ubiquitination can serve as an acute dynamic regulator of synaptic function. This represents a novel regulatory pathway that is of clear basic science interest given the central role of synaptic transmission in nervous system function. However, the pathway is also of clear clinical interest as it might offer insight into the earliest steps of dysfunction associated with neurodegenerative diseases. In many neurodegenerative diseases signs of synaptic dysfunction precede clinical symptoms. Neurodegenerative diseases are also characterized by a UPS that is impaired either through mutations in the pathway, by misfolded proteins or via environmental toxins. The recognition of the rapid regulatory role of the UPS in shaping synaptic transmission might offer an early causal link between UPS impairment and synaptic dysfunction. In this grant application we will test the physiological mechanisms that mediate the rapid regulation of presynaptic release by ubiquitination (Aim 1). Together with the identification of the synaptic ubiquitome (Aim2) these experiments will enable discovery of pathways and processes that are of basic science interest and that might provide novel druggable targets for neurological diseases. PUBLIC HEALTH RELEVANCE: In this grant application we propose to test the hypothesis that protein ubiquitination at the synapse can serve as a rapid, posttranslational modification that regulates synaptic transmission, rather than simply representing a signal for protein degradation by the proteasome. Early stages of many neurodegenerative diseases, such as Parkinson's, Alzheimer's and Huntington's Disease, are characterized by changes in synaptic function and protein ubiquitination is compromised either by mutations in the pathway or by accumulation of misfolded proteins. Our experiments on the role of rapid protein ubiquitination in the regulation of synaptic transmission suggest a causal link between these observations and thus indicate novel druggable targets and pathways.

描述（由申请人提供）：突触传递是神经系统的一个关键特征，因此在许多不同的时间尺度上受到严格的调节。泛素-蛋白酶体系统（UPS）通过维持适当的蛋白质稳态在突触传递中起着重要作用。在发育过程中，UPS通过塑造长期可塑性，通过改变活跃突触的数量和改变囊泡池的大小来调节突触的形成。所有这些调节功能都发生在数小时至数天的时间尺度上，并且与UPS在蛋白质降解中的中心作用一致：泛素标签蛋白的共价连接用于蛋白酶体的降解。我们最近发现，UPS也在几分钟或更短的时间内调节神经递质的释放，这使我们提出了这样的假设，即突触上的泛素化通过改变靶蛋白的活性水平而不是改变它们的半衰期来快速调节释放。因此，蛋白质泛素化可以作为突触功能的急性动态调节剂。这代表了一种新的调节途径，具有明确的基础科学兴趣，因为突触传递在神经系统功能中起着核心作用。然而，该途径也具有明确的临床意义，因为它可能提供与神经退行性疾病相关的功能障碍的最早步骤的见解。在许多神经退行性疾病中，突触功能障碍的迹象先于临床症状。神经退行性疾病的特征还在于UPS通过通路中的突变、通过错误折叠的蛋白质或通过环境毒素而受损。UPS在塑造突触传递中的快速调节作用的认识可能提供UPS损伤和突触功能障碍之间的早期因果关系。在这项资助申请中，我们将测试介导突触前释放的泛素化（目标1）的快速调节的生理机制。这些实验与突触泛素组（Aim 2）的鉴定一起，将能够发现具有基础科学意义的途径和过程，并可能为神经系统疾病提供新的药物靶点。 公共卫生相关性：在这项资助申请中，我们建议测试的假设，蛋白质泛素化在突触可以作为一个快速的，翻译后修饰，调节突触传递，而不是简单地代表蛋白酶体的蛋白质降解的信号。许多神经退行性疾病（例如帕金森氏病、阿尔茨海默氏病和亨廷顿氏病）的早期阶段的特征在于突触功能的变化，并且蛋白质泛素化受到通路中的突变或错误折叠蛋白质的积累的损害。我们对快速蛋白泛素化在突触传递调节中的作用的实验表明，这些观察结果之间存在因果关系，因此表明了新的药物靶点和途径。