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: 8286850
• 负责人: FELIX E SCHWEIZER
• 金额: $ 19.25万
• 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 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8286850
• 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.

描述（由申请人提供）：突触传播是神经系统的关键特征，并且在许多不同的时间尺度上受到了严格的调节。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播中起着重要作用。 UPS通过改变活性突触的数量和改变囊泡池的大小来调节发育过程中突触形成。所有这些调节功能都以小时到几天的时间范围出现，并且与UPS在蛋白质降解中的核心作用一致：泛素标签的共价附着蛋白质蛋白质因蛋白酶体而降解。我们最近发现，UPS还可以在几分钟或更短的时间尺度上调节神经递质的释放。这使我们提出了一个假设，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其半衰期来迅速调节释放。因此，蛋白质泛素化可以用作突触功能的急性动态调节剂。这是一种新型的调节途径，鉴于突触传播在神经系统功能中的核心作用，它具有明显的基础科学兴趣。但是，该途径也具有明显的临床兴趣，因为它可能会深入了解与神经退行性疾病相关的最早功能障碍步骤。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在于通过途径，错误折叠的蛋白或通过环境毒素在途径中的突变损害的UPS。对UPS在塑造突触传播中的快速调节作用的认识可能会在UPS损伤和突触功能障碍之间提供早期因果关系。在此赠款应用中，我们将测试通过泛素化迅速调节突触前释放的生理机制（AIM 1）。连同鉴定突触的泛素体（AIM2），这些实验将能够发现具有基础科学利益的途径和过程，这些途径和过程可能为神经系统疾病提供新颖的可药物目标。