Identifying mechanisms that regulate local axon vulnerability to pathological degeneration

神经退行性疾病是对人类健康的重大挑战。多种治疗策略 围绕着抑制神经元细胞体的死亡。然而，神经元的连接依赖于长时间 突起被称为轴突，它们使用专门的机制在远离胞体的情况下生存。这个 轴突变性在各种神经退行性疾病中是一种常见的、有时是起始的事件。 包括阿尔茨海默氏症、帕金森氏症和周围神经病。保护轴突健康是 对于维持功能连接是必要的，并将与许多疾病具有广泛的相关性。疾病 发病和严重程度在患者之间可能有很大差异，这表明存在重要的、未被发现的因素 这会影响轴突对病理性变性的易感性。这个项目的目标是定义小说 控制受损轴突命运的通路。轴突损伤刺激局部自毁机制， 通过免疫系统促进轴突的分解和清除。NMNat2和Sarm1酶 代表着这个自我毁灭计划中的一个关键监管节点。增强NMNA2具有神经保护作用 有治疗潜力。我们将定义一种新的机制来控制轴突片段中NMNA2的丰度。 我们还将确定自噬在轴突易感性和应激信号中的新贡献。这些研究 将对控制轴突健康的局部机制产生新的见解，并揭示新的治疗机会 神经退行性疾病。

Neurodegenerative disorders represent a significant challenge to human health. Many therapeutic strategies revolve around suppressing death of the neuronal cell body. However, neuronal connectivity depends on long projections called axons that use specialized mechanisms to survive in isolation from the soma. The degeneration of axons is a common, sometimes initiating event in a variety of neurodegenerative disorders including Alzheimer’s disease, Parkinson’s disease, and peripheral neuropathies. Protecting axon health is necessary for sustaining functional connectivity and will have broad relevance to many diseases. Disease onset and severity can vary significantly between patients suggesting there are important, undiscovered factors that influence axon vulnerability to pathological degeneration. The goal of this project is to define novel pathways controlling the fate of a damaged axon. Axon injury stimulates a local self-destruct mechanism that promotes axon dismantling and clearance by the immune system. The enzymes NMNAT2 and SARM1 represent a critical regulatory node in this self-destruction program. Boosting NMNAT2 is neuroprotective and has therapeutic potential. We will define a new mechanism controlling NMNAT2 abundance in axon segments. We will also identify new contributions for autophagy in axon susceptibility and stress signaling. These studies will generate new insight on local mechanisms controlling axon health and reveal new treatment opportunities in neurodegenerative diseases.