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The role of a novel viral-like signalling pathway in synaptic plasticity and neurological disorders

新型病毒样信号通路在突触可塑性和神经系统疾病中的作用

基本信息

批准号：
10430205
负责人：
Travis Thomson
金额：
$ 36.64万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10430205
关键词：
3&apos Untranslated Regions Actins Address Amino Acid Sequence Antibodies Behavior Binding Biological Models Capsid Cells Co-Immunoprecipitations Communication Cytoskeleton Degenerative Disorder Development Down-Regulation Drosophila genus Encapsulated Epilepsy Exhibits Genes Genetic Genome Goals Grant Homologous Gene Human Infectious Agent Learning Mammals Mediating Memory Messenger RNA Molecular Multivesicular Body Muscle Nervous system structure Neuromuscular Diseases Neuromuscular Junction Neuronal Plasticity Neurons Pathway interactions Physiological Play Presynaptic Terminals Proteins RNA RNA Interference RNA immunoprecipitation sequencing Reagent Reporting Research Reticulum Retrotransposon Role Schizophrenia Selfish Genes Signal Pathway Signal Transduction Spinocerebellar Ataxias Synapses Synaptic Vesicles Synaptic plasticity System Testing Transcript Transfer RNA Travel Uncertainty Ursidae Family Viral Viral Genome Virus WNT Signaling Pathway Work experimental study extracellular vesicles fly gag Gene Products human disease intercellular communication knock-down nervous system disorder neuromuscular neuron development neurotransmission novel particle postsynaptic presynaptic protein function trafficking viral RNA

项目摘要

We have discovered a novel viral-like signaling pathway associated with extracellular vesicles (EV). We found the Drosophila homolog of ARC (Actin-Regulated Cytoskeleton-associated protein) (darc1), is present in EVs as both an mRNA and protein. ARC is a master regulator of synaptic plasticity in the nervous system of mammals and is crucial for learning and memory. dArc1 bears a domain resembling retroviral/retrotransposon Gag-like proteins that multimerizes into a capsid that packages viral RNA. Our work shows dARC1 forms a capsid, associates with its own RNA, and then transports the darc1 transcript across the synapse. The transfer of dArc1 is needed for activity-dependent plasticity at the fly neuromuscular junction (NMJ). Besides dArc1, it is unknown whether other genes are in this viral-like pathway. We address this uncertainty in Aim 1. Here we describe our plan to identify other Gag-like proteins in EVs, and we have already found another Gag protein enriched in EVs, that is encoded by the retrotransposon Copia. We have found that Copia transfers across the synaptic bouton. When copia is knocked down at the NMJ this strikingly leads to increased plasticity. This is the opposite of darc1, where we reported a decrease in plasticity. In Aim 2 we focus on what cargoes are co-transferring with dArc1 and Copia. We have identified through co-immunoprecipitation, mRNAs and proteins that associate with dArc1 and Copia. As to how the transfer of Arc occurs, we have found that the dArc1 3’untranslated region (UTR) is necessary and sufficient for the transfer of dArc1 across synaptic boutons. We are now testing if the dArc1 3’UTR directs the loading of dArc1 into EVs. As well, we propose experiments to understand how darc1 and copia mediate synaptic plasticity. We have co-immunoprecipitated dArc1 and Copia to identify potential interactors, and we will take a candidate approach to find genetic interactors. In preliminary work we found that dArc1 is needed for proper WNT pathway signaling at the NMJ. Additionally, we observe that Copia and dArc1 bind to some of the same proteins and mRNAs, suggesting that they may be antagonistic to each other, thus potentially explaining their seemingly opposite roles in mediating plasticity. Through this grant we will expand our understanding of EV trafficking and synaptic plasticity, while describing a novel physiological function of a retrotransposon in neuronal communication.

我们发现了一种新的与细胞外囊泡（EV）相关的病毒样信号通路。我们