Molecular and genetic studies of NMNAT2 in neuroprotection

NMNAT2 神经保护作用的分子和遗传学研究

基本信息

批准号：
10378160
负责人：
HUI-CHEN LU
金额：
$ 59.14万
依托单位：
TRUSTEES OF INDIANA UNIVERSITY
依托单位国家：
美国
项目类别：
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/10378160
关键词：
ALS patients Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Alzheimer&apos s disease therapy American Amyloid beta-Protein Amyloid beta-Protein Precursor Attenuated Axon Axonal Transport Bayesian Analysis Biology Brain Bypass Chronic 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 (Brain)Homeostasis Human Huntington Disease Hyperactivity Image Impairment Inflammation Knockout Mice Knowledge Life Link Maintenance Metabolic Metabolic Pathway Metabolism Molecular Chaperones Molecular Genetics Mus Nerve Degeneration Neuraxis 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 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

项目摘要

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.

项目概要/摘要阿尔茨海默病的高患病率以及不断增加的社会和经济成本令人震惊 (AD) 和 AD 相关痴呆 (ADRD) 强调寻找预防或减缓其发生的策略的重要性在这里，我们的目标是阐明神经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治疗策略。出生在生命早期，需要积极的神经保护计划才能生存，以应对无数的情况 NMNAT2 是我们和他们在一生中面临的内部和外部挑战的双功能蛋白质。其他人已确定 NMNAT2 是合成烟酰胺的重要神经维持因子。单核苷酸 (NAD+) 并作为日常轴突功能的分子伴侣并保护来自蛋白病（例如过度磷酸化 tau）的神经元在 AD 患者中，NMNAT2 丰度为大大降低至正常水平的 50% 以下，我们发现其水平与认知功能相关。从小鼠皮质谷氨酸能神经元中删除 NMNAT2 会导致 AD/ADRD 样表型，例如葡萄糖代谢减退、轴突病变和神经炎症目前对小鼠和人类结果强烈。支持 NMNAT2 功能低下与神经退行性变之间的因果关系。轴突变性是 AD/ADRD 和许多神经退行性疾病的关键步骤。运输在神经功能和生存中发挥着关键作用，并且对能量的需求极其异常。轴突运输是轴突的一种早期缺陷，注定会退化。越来越多的证据表明轴突的失调。我们的初步研究表明，NMNAT2 在快速轴突中发挥着关键作用。删除谷氨酸能神经元中的 NMNAT2 会降低轴突能量稳态。糖酵解同时增强戊糖磷酸这些发现提出了以下结论。问题：谷氨酸能神经元中的 NMNAT2 在维持能量稳态方面发挥重要作用吗？轴突功能正常吗？ NMNAT2 缺失导致的葡萄糖代谢减退会导致轴突病变吗？绕过 NMNAT2 支持神经元并减轻轴突病变的补充策略？问题，我们提出以下目标： 1. 检验皮质神经元轴突运输需要 NMNAT2 的假设。 2. 检验 NMNAT2 有助于轴突能量稳态的假设。 3. 检验皮质神经元中的 NMNAT2 对于葡萄糖代谢至关重要的假设从我们提出的研究中获得的知识将帮助我们获得机制上的理解 NMNAT2 有助于主动神经维持，并将提供必要的见解来协助药物治疗使用 NMNAT2 作为神经退行性疾病治疗靶点的发现。