Defining the Mechanism of Alpha-synuclein Dependent Restriction of Viral Neuroinvasion

定义α-突触核蛋白依赖性限制病毒神经侵袭的机制

• 批准号: 9349196
• 负责人: John David Beckham
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9349196
• 关键词: Acute; Age; Americas; Antiviral Agents; Biological Assay; Brain; Brain Diseases; Brain region; Data; Diffuse; Disease; Disease Marker; Foundations; Growth; Health; Health Benefit; Herpesvirus 1; Human; Immune response; Immunohistochemistry; Immunoprecipitation; Individual; Infection; Innate Immune Response; Knock-out; Knockout Mice; Laboratories; Lewy Bodies; Lewy Body Dementia; Location; Measures; Membrane; Military Personnel; Molecular Virology; Mus; Mutation; Mutation Analysis; Nature; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurons; Neurovirology; Parkinson Disease; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Peripheral; Peripheral Nerves; Peripheral Nervous System; Phosphorylation; Polymerase Chain Reaction; Population; Populations at Risk; Positioning Attribute; Post-Translational Protein Processing; Prevention; Process; Proteins; Publishing; Research; Research Proposals; Risk; Role; Route; Serine; Site; Techniques; Time; Tissues; Transgenic Mice; Transgenic Organisms; United States; Veterans; Viral; Viral Antigens; Virus; Virus Diseases; Virus Replication; West Nile viral infection; West Nile virus; Work; alpha synuclein; brain tissue; gastrointestinal; immunocytochemistry; improved; insight; mortality; mouse model; novel; novel strategies; olfactory bulb; prevent; response; synucleinopathy

Alpha-synuclein (syn) is a neuron-specific protein known to cause Parkinson’s disease. The protein is always expressed and recent work has shown that syn mis-folds into fibrils in peripheral neurons in the gastrointestinal track and the olfactory bulb. These fibrils then spread to the central nervous system in select individuals resulting in neurodegenerative diseases like Parkinson’s disease or Diffuse Lewy Body Dementia. Veteran populations are at risk for developing neurodegenerative diseases as they age and work to understand the cause of Parkinson’s disease will yield new approaches to treat and prevent neurodegenerative diseases. We have discovered that virus infections initiate post-translational modifications of syn that are associated with Parkinson’s disease. Moreover, our prior work has shown that syn functions to inhibit virus infections from spreading from the peripheral nerves to the central nervous system. Taken together, our findings reveal a stunning new understanding of the role of syn in the brain. We hypothesize that viral infections induce post-translational modifications in syn as an antiviral mechanism. While this response is acutely protective, exposure increases the risk of syn-induced pathology that can result in long term neurodegenerative diseases found in Parkinson’s disease. We will evaluate our hypothesis by defining the mechanism of syn-induced inhibition of WNV infection in neurons and defining the interactions between syn post-translational modifications and α-syn fibril spread. We will utilize techniques in molecular virology in combination with established mouse models in the field of Parkinson’s research to define the specific interactions and consequences of the interactions between syn and viral infection in the brain. If the proposed studies are completed as outlined, we will provide novel data that will have significant impact on the field of Parkinson’s disease research and neurovirology. Thus, our proposed work will have significant benefits for our veteran populations by improving health and providing potential new approaches to prevent and treat neurodegenerative processes like Parkinson’s disease.

α-突触核蛋白（syn）是一种神经特异性蛋白，已知会引起帕金森氏病。蛋白质总是 表达和最近的工作表明，在外周神经元中的原纤维中误差折叠 胃肠道和嗅球。然后，这些原纤维在选择中扩散到中枢神经系统 导致神经退行性疾病等神经退行性疾病，例如帕金森氏病或弥漫性刘易体内痴呆。 退伍军人人口随着年龄的增长而患神经退行性疾病的风险 了解帕金森氏病的原因将产生新的方法来治疗和预防神经退行性 疾病。我们已经发现，病毒感染引发了对syn的翻译后修饰 与帕金森氏病有关。此外，我们先前的工作表明，syn功能抑制病毒 从外周神经系统传播到中枢神经系统的感染。 综上所述，我们的发现揭示了人们对syn在大脑中的作用的惊人新理解。我们 假设病毒感染诱导syn的翻译后修饰作为一种抗病毒机制。 尽管这种反应受到严格保护，但暴露会增加syn诱导的病理的风险 导致在帕金森氏病中发现的长期神经退行性疾病。我们将评估我们的假设 通过定义syn诱导的抑制神经元中WNV感染的机制并定义相互作用 syn的翻译后修饰与α-Syn原纤维扩散之间。我们将在分子中利用技术 病毒学结合帕金森研究领域的既定小鼠模型，以定义 大脑中的syn和病毒感染之间相互作用的特定相互作用以及后果。如果是 建议的研究按概述完成，我们将提供新的数据，这些数据将对该数据产生重大影响 帕金森氏病研究和神经病毒学领域。那，我们提议的工作将带来巨大的好处 对于我们的资深人口，通过改善健康并提供潜在的新方法来预防和治疗 神经退行性过程，例如帕金森氏病。