Molecular and genetic studies of NMNAT2 in neuroprotection

项目摘要/摘要 阿尔茨海默病的高患病率和不断增长的社会和经济成本 (AD)和AD相关痴呆(ADRD)强调找到预防或减缓其痴呆的策略的重要性 进步。在这里，我们旨在阐明神经元维持和能量动态平衡的基本生物学 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。几乎所有的神经元 在生命早期出生，需要积极的神经保护计划才能生存，以应对无数 他们一生中面临的内部和外部挑战。NMNA2是一种双功能蛋白质，我们和 其他人则认为这是一个重要的神经元维持因素。NMNA2合成烟酰胺 单核苷酸(NAD+)，作为分子伴侣参与轴突的日常功能和保护 来自蛋白质病的神经元，如过度磷酸化的tau。在AD患者中，NMNA2丰度为 极大地降低到正常水平的50%以下，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NMNA2会导致AD/ADRD样表型，如 葡萄糖代谢不足，轴索病变和神经炎症。目前的老鼠和人类的结果是强烈的 支持NMNA2功能低下和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。轴突 运输对神经元的功能和存活起着至关重要的作用，而且对能量的要求也非常高。异常 轴突运输是轴突的早期缺陷，注定要退化。越来越多的证据显示监管不力 阿尔茨海默病中的葡萄糖代谢。我们的初步研究表明，NMNA2在快轴突起中起着关键作用 通过维持轴突能量动态平衡进行运输。删除谷氨酸能神经元中的NMNA2会减少 糖酵解，同时增加戊糖磷酸。这些发现提出了以下结论 问题：谷氨酸能神经元中的NMNA2是否在维持脑内能量平衡方面发挥重要作用 轴突功能正常吗？NMNA2基因缺失引起的葡萄糖低代谢是否会导致轴索病变？将要 绕过NMNA2的补充策略支持神经元和减轻轴索病变？要回答这些问题 针对这些问题，我们提出了以下目标： 1.验证皮质神经元需要NMNA2进行轴突运输的假设。 2.验证NMNA2促进轴突能量稳态的假说。 3.检验大脑皮层神经元中NMNA2对葡萄糖代谢至关重要的假说 从我们提议的研究中获得的知识将帮助我们从机械上理解 NMNA2有助于积极的神经元维护，并将提供必要的见解，以协助药物 发现使用NMNA2作为治疗神经退行性变的靶点。

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.