Post-translational modifications of tomosyn and synaptic plasticity

断层合成和突触可塑性的翻译后修饰

• 批准号: 8720373
• 负责人: Johnny J. Saldate
• 金额: $ 3.36万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2018-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8720373
• 关键词: Affect; Alzheimer' s Disease; Autistic Disorder; Basic Science; Behavior; Biochemistry; Brain; Cell membrane; Cells; Characteristics; Chemicals; Cognition; Cognitive; Complex; Data; Degradation Pathway; Dementia; Development; Disease; Drug Formulations; Electrophysiology (science); Enzymes; Exocytosis; Foundations; Health; Homeostasis; Human; Huntington Disease; Image; Impaired cognition; Individual; Investigation; Learning; Link; Measurement; Mediating; Memory; Mental Health; Methods; Modification; Molecular; Molecular Biology; Motor; Mutation; Nerve; Nerve Degeneration; Nervous System Physiology; Neuraxis; Neuronal Plasticity; Neurons; Outcome; Parkinson Disease; Pathway interactions; Physiology; Post-Translational Protein Processing; Prevention; Probability; Process; Protein Family; Proteins; Regulation; Reporting; Research; Role; SNAP receptor; Signal Pathway; Signal Transduction; Synapses; Synaptic Transmission; Synaptic Vesicles; Synaptic plasticity; System; Testing; Therapeutic; Ubiquitin; Ubiquitination; Vesicle; Work; autism spectrum disorder; base; effective therapy; flexibility; fluorescence imaging; genetic manipulation; information processing; insight; multicatalytic endopeptidase complex; nervous system disorder; neural circuit; neurotransmission; neurotransmitter release; novel; presynaptic; protein degradation; protein protein interaction; public health relevance; relating to nervous system; research study; transmission process

DESCRIPTION (provided by applicant): Transmission of information through neural circuits at synapses is an essential requirement for cognition, learning, memory, and motor function. Synaptic transmission is not fixed but dynamically modifiable, a process referred to as synaptic plasticity. Exocytosis of synaptic vesicles is mediated by the SNARE family proteins which form trans-SNARE complexes between the vesicle and presynaptic plasma membrane. Formation of these SNARE complexes serves as a central regulated molecular mechanism underlying the efficacy of synaptic transmission. Tomosyn is a unique presynaptic R-SNARE protein in that it is cytosolic and serves as a potent negative regulator of exocytosis. The availability and activity-state of tomosyn in nerve terminals affects release probability by negatively regulating the priming of vesicles for release. What remains unknown are the molecular mechanisms and signaling pathways by which tomosyn activity is modulated. Provocative recent evidence suggests that the ubiquitin (Ub) and small ubiquitin-like modifier (SUMO) pathways exert particularly important influences on the modulation of synaptic strength. Remarkably, my preliminary evidence indicates that tomosyn protein levels and activity are subject to regulation by these distinct post-translational modifications. Therefore, I hypothesize that tomosyn's affects on synaptic plasticity are under dynamic modulation of the activity of these systems. I propose to test this hypothesis by employing a combination of genetic manipulations, biochemistry, fluorescence imaging, and electrophysiological measurements to delineate: 1) if tomosyn is subject to regulated degradation via the ubiquitin proteasome system (UPS), and 2) how sumoylation of tomosyn modulates its sub-cellular localization, protein-protein interactions, and functional activity. Specifically, these aims will determine the synaptic activity states that indue post-translational modification of tomosyn via Ub and SUMO, define the relationship between these modifications and changes in tomosyn's mechanism of activity, and link these activity alterations to functional changes in presynaptically- mediated plasticity induction. Successful completion of these aims will reveal novel insights into how neural plasticity is induced and regulated, including the effects by which, and extent of, tomosyn involvement in neural activity-induced changes in presynaptic plasticity and homeostasis. Data gathered will extend beyond basic science research by providing potential mechanistic targets for preventative and therapeutic approaches for diseases involving neurotransmission, including those recently linked to tomosyn- and UPS-mediated alterations in neurotransmission and human central nervous system function and health (e.g. autism-spectrum disorders and Alzheimer's disease).

描述（由申请人提供）：信息通过突触的神经回路传递是认知、学习、记忆和运动功能的基本要求。突触传递不是固定的，而是动态改变的，这一过程被称为突触可塑性。突触囊泡的胞吐是由SNARE家族蛋白介导的，该蛋白在囊泡和突触前质膜之间形成trans-SNARE复合物。这些SNARE复合物的形成是突触传递效力的核心调控分子机制。Tomosyn是一种独特的突触前R-SNARE蛋白，它是胞浆性的，是胞外分泌的一种有效的负调节因子。神经末梢断层同步蛋白的可用性和活性状态通过负向调节释放囊泡的启动来影响释放概率。目前尚不清楚的是调节tomosyn活性的分子机制和信号通路。最近有证据表明，泛素（Ub）和小泛素样修饰因子（SUMO）通路对突触强度的调节具有特别重要的影响。值得注意的是，我的初步证据表明，tomosyn蛋白水平和活性受到这些不同的翻译后修饰的调节。因此，我假设tomosyn的影响