Regulation of Axonal Signaling by Palmitoylation

棕榈酰化对轴突信号传导的调节

基本信息

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
项目类别：
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

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

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项目摘要

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.

项目摘要该项目的长期目标是定义支配长距离转移的分子机制轴突中的蛋白质信号。逆行（轴突对瘤）信号对于激活转录至关重要在神经发育期间和神经损伤之后的程序，同时进行持续顺序（soma to-to-to-to 轴突的供应“轴突生存因子”对于维持远端轴突完整性至关重要。我们和其他人发现传达这些逆行和顺行信号的关键蛋白质通过脂质棕榈酸酯修饰，这有助于他们在轴突囊泡上的贩运。特别是，在资金的第一个周期中进行实验揭示了双亮氨酸Zipper激酶（DLK，上游激活剂（A MAP3K'）的逆行信号传导有丝分裂原激活的蛋白激酶（MAPK）途径）严重需要棕榈酰化。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。第一个目标将重点放在 JNK家族MAPK的棕榈酰化，这是DLK和其他MAP3KS下游的关键“效应器”激酶。我们将确定是否需要神经特异性JNK3的棕榈酰化。远端轴突以及JNK3是否磷酸化棕榈酰化的轴突存活因子，触发其通过新型的磷酸依赖机制降解。 AIM 2将重点放在Rap2上，这是一种小说的棕榈酰化位于DLK上游的调节器，并将确定Rap2及其棕榈酰化是否广泛 DLK依赖性逆行信号所需。 AIM 3将评估是否具有独特的可逆性与其他蛋白质脂质修饰相比，棕榈酰化可用于促进“寿司带运输” 钥匙轴突生存因子NMNAT2经历了棕榈酰化依赖性的顺序运输然后将囊泡局部局部二膜酰胺酰化，以增加其酶促和轴向保护活性。提议研究将定义新的细胞和分子作用，用于轴突蛋白运输和信号传导，并将提供有关轴突损伤反应如何协调和控制的关键见解。我们的研究结果还可能揭示轴突蛋白传输和信号传导的更广泛的原理增加我们对这些过程的神经退行性疾病的理解受损。