Regulation of Axonal Signaling by Palmitoylation

棕榈酰化对轴突信号传导的调节

• 批准号: 10450111
• 负责人: Gareth Thomas
• 金额: $ 39.63万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10450111
• 关键词: Acute; Acyltransferase; Address; Axon; Biological Assay; Biology; Distal; Elements; Enzymes; Equilibrium; Family; Funding; Genetic; Genetic Transcription; Goals; Impairment; Injury; Knockout Mice; Leucine Zippers; Lipids; MAPK10 gene; MAPK8 gene; MAPK9 gene; Maintenance; Mediating; Mitogen-Activated Protein Kinases; Modeling; Modification; Molecular; Monomeric GTP-Binding Proteins; N-terminal; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Palmitates; Pathway interactions; Pharmacology; Phosphorylation; Phosphotransferases; Play; Process; Property; Proteins; Regulation; Research; Retinal Ganglion Cells; Role; Signal Pathway; Signal Transduction; Site; Spinal Ganglia; Stimulus; Testing; Variant; Vesicle; Viral; Wallerian Degeneration; Work; axon injury; base; conditional knockout; deprivation; experimental study; in vivo; injured; insight; knock-down; mutant; nerve injury; neurodevelopment; neuronal cell body; neurotransmission; novel; novel therapeutics; overexpression; palmitoylation; programs; protein transport; relating to nervous system; response; small hairpin RNA; trafficking; ubiquitin ligase

Project Summary The long-term goal of this project is to define molecular mechanisms that govern the long distance transfer of protein-based signals in axons. Retrograde (axon-to-soma) signals are critical to activate transcriptional programs both during neurodevelopment and following nerve injury, while continuous anterograde (soma-to- axon) supply of `axon survival factors' is essential to maintain distal axon integrity. We and others have found that key proteins that convey these retrograde and anterograde signals are modified with the lipid palmitate, which facilitates their trafficking on axonal vesicles. In particular, experiments in the first cycle of funding revealed that retrograde signaling by Dual Leucine-zipper Kinase (DLK, an upstream activator (a `MAP3K') of Mitogen-activated Protein Kinase (MAPK) pathways) critically requires palmitoylation. We now hypothesize that palmitoylation more broadly controls several distinct aspects of axonal signaling. The first Aim will focus on palmitoylation of JNK family MAPKs, which are key `effector' kinases downstream of DLK and other MAP3Ks. We will determine whether palmitoylation of the neural-specific JNK3 is required for Wallerian degeneration of distal axons, and whether JNK3 phosphorylates palmitoylated axon survival factors, triggering their degradation via a novel phospho-dependent mechanism. Aim 2 will focus on Rap2, a novel palmitoylated regulator that lies upstream of DLK, and will determine whether Rap2 and its palmitoylation are broadly required for DLK-dependent retrograde signaling. Aim 3 will assess whether the unique reversibility of palmitoylation, compared with other protein-lipid modifications, is used to facilitate `sushi belt transport' whereby the key axon survival factor NMNAT2 undergoes palmitoylation-dependent anterograde trafficking on vesicles and is then locally depalmitoylated to increase its enzymatic and axo-protective activity. The proposed research will define new cellular and molecular roles for palmitoylation in axonal protein trafficking and signaling and will provide key insights into how responses to axonal damage are coordinated and controlled. Results of our study may also reveal broader principles of axonal protein transport and signaling, in turn increasing our understanding of a range of neurodegenerative disorders in which these processes are impaired.

项目摘要 这个项目的长期目标是定义管理长距离转移的分子机制。 轴突中基于蛋白质的信号。逆行(轴突到胞体)信号是激活转录的关键 在神经发育期间和神经损伤后的计划，而持续顺行(SOMA-to- 轴突)供应‘轴突存活因子’对于维持远端轴突的完整性是必不可少的。我们和其他人发现 传递这些逆行和顺行信号的关键蛋白质是用棕榈酸脂修饰的， 这促进了它们在轴突小泡上的运输。特别是，第一个筹资周期中的试验 双亮氨酸拉链酶(DLK，一种上游激活因子，MAP3K)的逆行信号转导 丝裂原活化蛋白激酶(MAPK)通路是棕榈酰化的关键途径。我们现在假设 棕榈酰化更广泛地控制轴突信号的几个不同方面。第一个目标将集中在 JNK家族MAPK的棕榈酰化，它是DLK和其他MAP3K下游的关键的“效应者”激酶。 我们将确定神经特异性JNK3的棕榈酰化是否是沃勒变性所必需的 远端轴突，以及JNK3是否磷酸化棕榈酰化轴突存活因子，触发其 通过一种新的磷依赖机制进行降解。目标2将专注于Rap2，一种新型的棕榈酰化 位于DLK上游的调节子，将决定Rap2及其棕榈酰化是否广泛 依赖DLK的逆行信号转导所需。目标3将评估是否具有独特的可逆性 与其他蛋白质-脂类修饰相比，棕榈酰化用于促进“寿司带运输”。 因此，关键的轴突生存因子NMNA2经历棕榈酰化依赖的顺行转运 囊泡，然后局部去甲基化以增加其酶活性和轴突保护活性。建议数 研究将确定棕榈酰化在轴突蛋白运输中的新的细胞和分子作用 并将为如何协调和控制对轴突损伤的反应提供关键见解。 我们的研究结果也可能揭示轴突蛋白运输和信号转导的更广泛的原理。 增加我们对一系列神经退行性疾病的了解，在这些疾病中，这些过程是 受伤了。