Mode of action of a neuroprotective compound

神经保护化合物的作用方式

• 批准号: 9234602
• 负责人: Corinne Ida Lasmezas
• 金额: $ 19.2万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9234602
• 关键词: ADP ribosylation; Affinity; Aftercare; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Axotomy; Beta Carbolines; Biological Assay; Biotin; Brain; Brain Ischemia; Cell Survival; Cells; Chemicals; Consumption; Data; Degradation Pathway; Development; Disease; Enzymes; Family; Frontotemporal Dementia; Future; Genetic; Huntington Disease; Injury; Ion Channel; Knowledge; Label; Lead; Link; Mass Spectrum Analysis; Metabolism; Methods; Modeling; Molecular; Molecular Target; Mono-S; Morphology; Multiple Sclerosis; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neuroprotective Agents; Oxidative Stress; Parkinson Disease; Pathogenesis; Pathway interactions; Pharmacology; Preclinical Drug Evaluation; Prion Diseases; Prions; Proteins; Proteomics; Psychotropic Drugs; Reaction; Recombinants; Recovery; Reperfusion Injury; Research; Rodent Model; Role; Series; Structure; Structure-Activity Relationship; Testing; Toxic effect; Wallerian Degeneration; analog; base; carboxylate; excitotoxicity; experimental study; genetic manipulation; high throughput screening; injured; insight; motor function improvement; mouse model; neuroblastoma cell; neuron loss; new therapeutic target; overexpression; programs; protein misfolding; public health relevance; small molecule

 DESCRIPTION (provided by applicant): NAD+ depletion causes neuronal death in rodent models of brain ischemia/reperfusion injury, Wallerian degeneration, multiple sclerosis and occurs after excitotoxic insults and oxidative stress. We have recently discovered that NAD+ depletion is also the primary cause of neuronal death induced by a misfolded and toxic form of the amyloidogenic prion protein (TPrP). These results established the role of NAD+ depletion in the pathogenesis of at least one protein misfolding neurodegenerative disease, a family of diseases that comprise, among others, Alzheimer's disease and Parkinson's disease. NAD+ replenishment reversed the fate of TPrP- injured neurons in culture and improved motor function in a mouse model of prion disease. In a pilot high- throughput screen we identified a compound restoring neuronal viability by NAD+ replenishment in TPrP- exposed cells. We hypothesize that its molecular target is a key effector in the TPrP-induced pathway and that deciphering the compound's mode of action will further our understanding of the mechanisms of NAD+ depletion prevalent in TPrP toxicity and possibly other debilitating brain conditions. In this focused research effort, we will use affinity-based methods combined with proteomics to identify the compound's molecular target relevant to its neuroprotective activity, determine its mode of action and probe its structure for enhanced activity. This knowledge will provide insights into degenerative pathways linked to NAD+ depletion and will support lead development efforts aiming at developing a neuroprotective drug.

 描述（由申请人提供）：NAD+耗竭导致啮齿类动物脑缺血/再灌注损伤、沃勒变性、多发性硬化症模型中的神经元死亡，并在兴奋性毒性损伤和氧化应激后发生。我们最近发现 NAD+ 耗竭也是由错误折叠且有毒的淀粉样蛋白朊病毒蛋白 (TPrP) 诱导的神经元死亡的主要原因。这些结果确定了 NAD+ 耗竭在至少一种蛋白质错误折叠神经退行性疾病发病机制中的作用，该疾病是一个疾病家族，其中包括阿尔茨海默病和帕金森病。补充 NAD+ 可以逆转培养物中 TPrP 损伤神经元的命运，并改善朊病毒病小鼠模型的运动功能。在试点高通量筛选中，我们发现了一种通过补充 TPrP 暴露细胞中的 NAD+ 来恢复神经元活力的化合物。我们假设其分子靶标是 TPrP 诱导途径中的关键效应子，破译该化合物的作用模式将进一步加深我们对 TPrP 毒性和可能的​​其他衰弱性脑部疾病中普遍存在的 NAD+ 消耗机制的理解。在这项重点研究工作中，我们将使用基于亲和力的方法与蛋白质组学相结合来识别该化合物与其神经保护活性相关的分子靶标，确定其作用模式并探测其结构以增强活性。这些知识将提供对与 NAD+ 消耗相关的退行性途径的见解，并将支持旨在开发神经保护药物的先导开发工作。