Defining TMEM184b-Controlled Pathways in Nerve Terminal Maintenance and Axon Degeneration

定义神经末梢维护和轴突变性中 TMEM184b 控制的通路

基本信息

批准号：
9919006
负责人：
Martha Ruth Chase Bhattacharya
金额：
$ 37.65万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9919006
关键词：
Address Affect Alzheimer&apos s Disease Amino Acids Amyotrophic Lateral Sclerosis Autophagocytosis Autophagosome Axon Axonal Transport Behavior Behavioral Biochemical Biochemistry Biological Biotinylation Cell Survival Cells Cellular biology Cessation of life Charcot-Marie-Tooth Disease Cyclic AMP Data Defect Diabetes Mellitus Diabetic Neuropathies Disease Drosophila genus Eating Electrophysiology (science)Event G-Protein-Coupled Receptors Genetic Genetic Diseases Genetic Epistasis Goals Impairment Inherited Injury Integral Membrane Protein Knowledge Label Life Link Lysosomes MAP Kinase Gene Maintenance Measurement Mediator of activation protein Metabolic stress Mitogen-Activated Protein Kinases Mitotic Modeling Molecular Molecular Analysis Motor Mus Muscle Mutant Strains Mice Natural regeneration Nerve Nerve Block Nerve Crush Nervous system structure Neuraxis Neurodegenerative Disorders Neurons Optic Nerve Organelles Pain Pathway interactions Peripheral Peripheral Nerves Peripheral Nervous System Pharmaceutical Preparations Phenotype Plant Roots Play Process Proteins Research Role Sensory Signal Pathway Signal Transduction Societies Stress Structure Symptoms Synapses Synaptic Transmission System Tactile Testing Tissues Traumatic injury Wallerian Degeneration Work afferent nerve axonal degeneration base beta-arrestin chemotherapy chemotherapy induced neuropathy fly follow-up functional restoration genetic analysis in vitro Assay injured multicatalytic endopeptidase complex mutant nerve injury nervous system disorder neuromuscular neurotoxicity novel p38 Mitogen Activated Protein Kinase pain behavior preservation prevent protein protein interaction recruit response to injury synaptic function therapy design

项目摘要

The overall objective of our work is to understand how nerve terminals and axons are maintained throughout life and how they respond to injury. In the peripheral nervous system (PNS), long primary motor and sensory axons and their terminals are susceptible to a wide variety of pro-degenerative insults, including metabolic stress during diabetes, neurotoxicities of chemotherapy drugs, traumatic injuries, and genetic disorders including Charcot-Marie-Tooth and Amyotrophic Lateral Sclerosis (ALS). In these disorders, terminals and axons are often the first affected structures, and their degeneration precedes cell body death. By mapping out the cellular, genetic, and biochemical landscape of the early events of nerve terminal and axon degeneration, we might identify ways to delay or prevent this degeneration in neurodegenerative disorders. We are focused on the axonal and synaptic functions of TMEM184b, a newly discovered 7-pass transmembrane protein, in the PNS. Loss of TMEM184b in mice causes progressive dystrophies in both motor and sensory nerve terminals, and also causes sensorimotor deficits. In addition to these nerve terminal phenotypes, reduction of TMEM184b in Drosophila or in mice leads to prolonged axon integrity after injury, suggesting TMEM184b is active in the axon degeneration cascade. Accumulations of autophagosomes and lysosomes, compartments responsible for protein and organelle degradation, are seen in mutant tissues. Based on these data, we hypothesize that TMEM184b regulates a step in autophagy. Because autophagy is known to promote axon degeneration and also alter synapse structure, this hypothesis would explain both the axon and synapse phenotypes of TMEM184b mutant mice. Using both mouse and Drosophila systems, we will test our hypothesis with a combination of molecular and genetic analysis, electrophysiology, cell biology, and behavior. In Aim 1, we will ascertain the root causes of the sensorimotor deficits seen in both flies and mice lacking TMEM184b by investigating neuromuscular synaptic transmission and sensory transduction, molecularly characterizing terminal dystrophies, and evaluating peripheral nerve axon transport. In Aim 2, we will probe the cellular and molecular pathways controlled by TMEM184b in cultured neurons and explanted tissues, with a particular focus on linking TMEM184b biological activity to the control of autophagy. In Aim 3, we will identify how TMEM184b contributes to pro-degenerative pathways in injured nerves using genetic epistasis and biochemistry, and we will ask whether TMEM184b's role in axon degeneration is conserved in the central nervous system. In summary, our research will describe a new mechanism of autophagy control in neurons that may underlie early stages of neurodegenerative diseases. This work will contribute to the discovery of new strategies to block nerve terminal and axon degeneration in neurodegenerative disorders.

我们工作的总体目标是了解神经末梢和轴突在整个过程中是如何维持的生活以及他们如何应对伤害。在周围神经系统 (PNS) 中，长初级运动和感觉轴突及其末端容易受到各种促退行性损伤，包括代谢应激糖尿病、化疗药物的神经毒性、创伤性损伤和遗传性疾病，包括腓骨肌萎缩症和肌萎缩侧索硬化症 (ALS)。在这些疾病中，末梢和轴突通常是首先受影响的结构，其退化先于细胞体死亡。通过绘制蜂窝图，神经末梢和轴突变性早期事件的遗传和生化景观，我们可能找出延迟或预防神经退行性疾病中这种退化的方法。我们专注于 TMEM184b 的轴突和突触功能，这是一种新发现的 7-pass 跨膜蛋白，位于三七总皂甙中。小鼠中 TMEM184b 的缺失会导致两侧运动神经进行性营养不良和感觉神经末梢，也会导致感觉运动缺陷。除了这些神经末梢表型，果蝇或小鼠中 TMEM184b 的减少会导致损伤后轴突完整性的延长，表明 TMEM184b 在轴突变性级联中具有活性。自噬体的积累和溶酶体是负责蛋白质和细胞器降解的区室，在突变组织中可见。基于根据这些数据，我们假设 TMEM184b 调节自噬的一个步骤。因为自噬已知促进轴突变性并改变突触结构，该假设可以解释轴突和突触结构 TMEM184b 突变小鼠的突触表型。使用小鼠和果蝇系统，我们将结合分子和果蝇系统来检验我们的假设。遗传分析、电生理学、细胞生物学和行为。在目标 1 中，我们将查明问题的根本原因通过研究神经肌肉突触，在缺乏 TMEM184b 的果蝇和小鼠中发现感觉运动缺陷传输和感觉转导，分子表征终末营养不良，并评估周围神经轴突运输。在目标 2 中，我们将探究由以下因素控制的细胞和分子途径： TMEM184b 在培养的神经元和外植组织中的应用，特别关注将 TMEM184b 生物活性来控制自噬。在目标 3 中，我们将确定 TMEM184b 如何促进促退行性变使用遗传上位性和生物化学研究受损神经的通路，我们将询问 TMEM184b 的作用是否轴突变性在中枢神经系统中是保守的。总之，我们的研究将描述神经元自噬控制的新机制，这可能是神经退行性疾病的早期阶段。这项工作将有助于发现新的策略来阻止神经退行性疾病中的神经末梢和轴突变性。