Molecular and genetic studies of NMNAT2 in neuroprotection

项目总结/摘要 阿尔茨海默病的高发病率和日益增加的发病率以及惊人的社会和财政成本 (AD)和AD相关痴呆（ADRD）强调了寻找预防或减缓其发病的策略的重要性。 进展在这里，我们的目标是阐明神经元维持和能量稳态的基础生物学， 使我们能够设计新的治疗策略，而不依赖于tau蛋白或β-淀粉样蛋白理论。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，以应对各种各样的 他们一生中面临的内部和外部挑战。NMNAT 2是一种双功能蛋白，我们和 其他人已经确定为重要的神经元维持因子。NMNAT 2合成烟酰胺 单核苷酸（NAD+），并作为一个分子伴侣的日常轴突功能，并保护 神经元从蛋白质病，如过度磷酸化的tau蛋白。在AD患者中，NMNAT 2丰度是 大大降低到正常水平的50%以下，其水平与认知功能相关。我们发现 从小鼠皮层神经元中删除NMNAT 2导致AD/ADRD样表型，例如 葡萄糖代谢低下、轴突病和神经炎症。目前的小鼠和人类结果强烈 支持NMNAT 2功能减退和神经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 转运在神经元功能和存活中起关键作用，并且对能量要求极高。异常 轴突运输是注定退化的轴突的早期缺陷。越来越多的证据表明， AD中的糖代谢。我们的初步研究表明，NMNAT 2在快速轴突生长中起着关键作用。 通过维持轴突能量稳态进行运输。在多巴胺能神经元中删除NMNAT 2减少了 糖酵解，同时增加戊糖磷酸。这些调查结果提出了以下问题 问题：海马能神经元中的NMNAT 2在维持能量稳态中发挥重要作用吗？ 轴突功能正常吗NMNAT 2缺失引起的葡萄糖代谢低下会导致轴突病吗？将 补充策略绕过NMNAT 2支持神经元和衰减轴突病变？回答这些 问题，我们提出以下目标： 1.检验NMNAT 2在皮层神经元轴突运输中所需的假设。 2.测试NMNAT 2有助于轴突能量稳态的假设。 3.测试皮质神经元中的NMNAT 2对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对如何 NMNAT 2有助于活跃的神经元维持，并将提供必要的见解，以协助药物治疗。 使用NMNAT 2作为神经变性的治疗靶点的发现。

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.