Molecular and genetic studies of NMNAT2 in neuroprotection

NMNAT2 神经保护作用的分子和遗传学研究

• 批准号: 10579950
• 负责人: HUI-CHEN LU
• 金额: $ 51.27万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579950
• 关键词: ALS patients; Acceleration; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease therapy; American; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Attenuated; Axon; Axonal Transport; Bayesian Analysis; Biology; Brain; Bypass; Central Nervous System; Chronic; Compensation; Data; Defect; Development; Disease model; Down-Regulation; Energy Supply; Enzymes; Face; Financial cost; Genes; Genetic study; Gliosis; Glucose; Glutamate-ammonia-ligase adenylyltransferase; Glutamates; Glycolysis; Goals; Golgi Apparatus; Health; Hippocampus; Homeostasis; Human; Huntington Disease; Hyperactivity; Image; Impairment; Inflammation; Knockout Mice; Knowledge; Life; Link; Maintenance; Metabolic; Metabolic Pathway; Metabolism; Molecular; Molecular Chaperones; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nicotinamide Mononucleotide; Nicotinamide adenine dinucleotide; Oxidative Phosphorylation; Parkinson Disease; Pathology; Pentosephosphates; Phenotype; Play; Prevalence; Process; Proteins; Proteolytic Processing; Resolution; Risk Factors; Role; Spinal Cord; Supplementation; Synaptic Transmission; Synaptic Vesicles; Testing; Therapeutic; Time; Up-Regulation; Visualization; amyloid precursor protein processing; axonal degeneration; axonopathy; brain metabolism; cofactor; cognitive function; combat; design; drug discovery; fast axonal transport; glucose metabolism; hyperphosphorylated tau; in vivo; insight; metabolomics; neuroinflammation; neuroprotection; nicotinamide riboside supplementation; novel; novel therapeutic intervention; prevent; programs; public health relevance; response; sensor; social; synaptogenesis; tau Proteins; theories; therapeutic target; therapy development

PROJECT SUMMARY / ABSTRACT The high and increasing prevalence as well as the staggering social and financial costs of Alzheimer’s Disease (AD) and AD-related dementia (ADRD) emphasize the importance of finding strategies to prevent or slow their progression. Here we aim to elucidate the basic biology of neuronal maintenance and energy homeostasis to enable us to design new therapeutic strategies independent of tau or beta-amyloid theories. Almost all neurons are born early in life and require an active neuroprotection program for their survival in response to the myriad of internal and external challenges they face throughout life. NMNAT2 is a bifunctional protein that we and others have identified as an important neuronal maintenance factor. NMNAT2 synthesizes nicotinamide mononucleotide (NAD+) and serves as a molecular chaperone for day-to-day axonal function and to protect neurons from proteinopathies such as hyperphosphorylated tau. In AD patients, NMNAT2 abundance is greatly reduced to less than 50% of normal level and its level correlates with cognitive function. We found that deleting NMNAT2 from mouse cortical glutamatergic neurons results in AD/ADRD-like phenotypes, such as glucose hypometabolism, axonopathy and neuroinflammation. The current mouse and human results strongly support a causal relationship between NMNAT2 hypofunction and neurodegeneration. Axonal degeneration is a key step in AD/ADRD and many neurodegenerative diseases. Axonal transport plays critical roles in neuronal function and survival and is extremely energy demanding. Abnormal axonal transport is an early defect in axons destined to degenerate. Increasing evidence reveals dysregulated glucose metabolism in AD. Our preliminary studies suggest that NMNAT2 plays a critical role in fast axonal transport by maintaining axonal energy homeostasis. Deleting NMNAT2 in glutamatergic neurons reduces glycolysis while at the same time augmenting the pentose phosphate. These findings raise the following questions: Does NMNAT2 in glutamatergic neurons play essential roles in maintaining energy homeostasis for normal axonal function? Does glucose hypometabolism caused by loss of NMNAT2 cause axonopathy? Will supplement strategies bypassing NMNAT2 support neurons and attenuate axonopathy? To answer these questions, we propose the following aims: 1. Test the hypothesis that NMNAT2 is required in cortical neurons for axonal transport. 2. Test the hypothesis that NMNAT2 contributes to axonal energy homeostasis. 3. Test the hypothesis that NMNAT2 in cortical neurons is essential for glucose metabolism The knowledge gained from our proposed studies will help us gain mechanistic understanding into how NMNAT2 contributes to active neuronal maintenance and will provide necessary insights to assist in drug discovery using NMNAT2 as a therapeutic target for neurodegeneration.

项目摘要 /摘要 阿尔茨海默氏病的高潮和日益增加的社会和经济成本 （AD）和与广告相关的痴呆症（ADRD）强调寻找预防或减慢其减慢策略的重要性 进展。在这里，我们旨在阐明神经元维持和能量稳态的基本生物学 使我们能够设计独立于TAU或β-淀粉样蛋白理论的新的治疗策略。几乎所有神经元 生于生命的早期，需要一个积极的神经保护计划才能响应其生存 他们一生都面临的内部和外部挑战。 NMNAT2是我们和 其他人则被认为是重要的神经元维持因子。 NMNAT2合成烟酰胺 单核苷酸（NAD+），并用作日常轴突功能的分子伴侣 来自蛋白质病的神经元，例如热磷酸化的tau。在AD患者中，NMNAT2抽象是 大大降低到正常水平的不到50％，其水平与认知功能相关。我们发现 从小鼠皮质谷氨酸能神经元中删除NMNAT2会导致AD/ADRD样表型，例如 葡萄糖低代谢，轴突病和神经炎症。当前的老鼠和人类结果强烈 支持NMNAT2功能障碍与神经退行性变性之间的因果关系。 轴突变性是AD/ADRD和许多神经退行性疾病的关键步骤。轴突 运输在神经元功能和生存中起关键作用，并且需要极大的能量。异常 轴突运输是轴突的早期缺陷。越来越多的证据表明失调 AD中的葡萄糖代谢。我们的初步研究表明，NMNAT2在快速轴突中起关键作用 通过维持轴突能量稳态来运输。删除谷氨酸能神经元中的NMNAT2减少 糖酵解同时增强五磷酸五磷酸盐。这些发现提出了以下内容 问题：谷氨酸能神经元中的NMNAT2在维持能量稳态方面起着重要作用 正常的轴突功能？由NMNAT2失去引起的葡萄糖低代谢会导致轴突病吗？将要 绕过NMNAT2支持神经元并减弱轴突病的补充策略？回答这些 问题，我们提出以下目的： 1。检验假说，即在皮质神经元中需要NMNAT2才能进行轴突运输。 2。检验NMNAT2有助于轴突能稳态的假设。 3。检验假设，即皮质神经元中的NMNAT2对于葡萄糖代谢至关重要 从我们提出的研究中获得的知识将有助于我们对 NMNAT2有助于主动神经元维持，并将提供必要的见解以帮助药物 使用NMNAT2作为神经退行性的治疗靶标。