Molecular and genetic studies of NMNAT2 in neuroprotection

描述(由申请人提供)：正常的大脑功能需要一个积极的维护计划来维持神经元健康。从本质上讲，神经元和神经胶质细胞必须修复由神经元活动、损伤、毒素和衰老引起的损伤。环境应激源影响 如果保护机制被削弱，则会导致神经系统功能障碍和变性。最近的研究表明，NMNAs(烟酰胺单核苷酸腺苷转移酶)在一生中维持神经元的完整性并促进正常的神经功能。NMNA2是在哺乳动物脑中表达的主要NMNAT亚型，在神经元中的半衰期很短，非常不稳定。我们和其他人发现，阿尔茨海默病、肥胖症或帕金森病患者的中枢神经系统组织中NMNA2水平显著降低。降低小鼠的NMNA2功能会导致轴突恶化，而NMNA2的过度表达则提供了神经保护。在拟议的工作中，我们将解决三个具体目标：NMNA2如何减少有毒tau物种，并保护神经元免受tau病的影响？NMNA2是否需要维持成人大脑中的神经元健康？小分子上调NMNA2水平是否具有神经保护作用？将结合分子/生化、遗传学、解剖学、电生理学、成像、病毒载体和高通量筛选方法来实现这些目标。这项研究将为NMNA2如何维持成熟大脑中的神经元健康提供洞察力。NMNAs是神经退行性变治疗干预的潜在药物靶点。详细了解NMNA2如何维持神经元的完整性及其在神经保护中的作用不仅对于了解正常的大脑功能至关重要，而且还将为药物开发提供必要的见解。

DESCRIPTION (provided by applicant): Proper brain function requires an active maintenance program to sustain neuronal health. In essence, neurons and glia have to repair the damage that is induced by neuronal activity, injury, toxins, and aging. Environmental stressors impact the nervous system and lead to neuronal dysfunction and degeneration if the protective mechanisms are weakened. Recent studies revealed that NMNATs (nicotinamide mononucleotide adenylyl transferase) maintain neuronal integrity and facilitate proper neural function throughout life. NMNAT2 is the major NMNAT isoform expressed in the mammalian brain and is extremely labile with a short half-life in neurons. We and others have found that NMNAT2 levels are significantly reduced in CNS tissues from patients with Alzheimer's disease, tauopathies, or Parkinson's disease. Reducing NMNAT2 function in mice leads to axonal deterioration, while NMNAT2 overexpression offers neuroprotection. In the proposed work we will address three specific aims: How does NMNAT2 reduce toxic tau species and protect neurons against tauopathy? Is NMNAT2 required to maintain neuronal health in adult brains? Is small molecule up-regulation of NMNAT2 levels neuroprotective? A combination of molecular/biochemical, genetic, anatomical, electrophysiological, imaging, viral vector and high-throughput screening approaches will be employed to accomplish these aims. This study will provide insight into how NMNAT2 maintains neuronal health in mature brains. NMNATs are potential drug targets for therapeutic interventions in neurodegeneration. A detailed knowledge on how NMNAT2 maintain neuronal integrity and its role in neuroprotection is critical not only for understanding normal brain function, but will also provide necessary insights to assist in drug discovery.