Elucidating the Trophic Support of Long Axons by Metabolic Signaling in Oligodendrocytes

通过少突胶质细胞代谢信号阐明长轴突的营养支持

• 批准号: 10782630
• 负责人: Bogdan Beirowski
• 金额: $ 37.49万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-09 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10782630
• 关键词: 5' -AMP-activated protein kinase; Adult; Alzheimer' s Disease; Attenuated; Axon; Biological; Central Nervous System; Cessation of life; Data; Defect; Deterioration; Diameter; Disease; Electrophysiology (science); Energy Metabolism; Etiology; Failure; Fiber; GLC2 protein; Genetic; Glean; Glucose; Health Promotion; Homeostasis; Impairment; Individual; Intoxication; Life Expectancy; Metabolic; Metabolic Pathway; Metabolism; Microfluidic Microchips; Mitochondria; Modeling; Molecular; Multiple Sclerosis; Mutant Strains Mice; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurologic; Oligodendroglia; Optic Nerve; Output; Pathway interactions; Phenotype; Phosphorylation; Phosphotransferases; Play; Regulation; Role; STK11 gene; Schwann Cells; Secondary to; Signal Pathway; Signal Transduction; Structure; Therapeutic; Work; axon injury; axonal degeneration; deprivation; disability; imaging modality; in vivo; interdisciplinary approach; lipid metabolism; liver ablation; metabolome; mitochondrial metabolism; mouse model; mutant; myelination; neural circuit; new therapeutic target; novel; preservation; sensor; therapeutic target; tool; upstream kinase; white matter

The fundamenal neuroscientific question as to how myelinating glia promote the health of long axons is greatly understudied. Axons are a particularly vulnerable component of neural circuits that are irreversibly damaged in early stages of many debilitating neurodegenerative conditions such as Multiple sclerosis and Alzheimers’ disease. The mechanisms underlying glial contributions to axonal injury are only pooly understood. Oligodendrocytes (OLGs), the myelinating glia of the central nervous system, stabilize axonal integrity by poorly understood trophic mechanisms. Current models suggest that glial metabolism is critical for this support function, and disrupted metabolic exchange between OLGs and axons, or metabolic deficits in OLGs may lead to axonal degeneration. In support, we made the exciting discovery that the LKB1 (liver kinase B1) signaling pathway is a crucial metabolic regulator in OLGs, and the inactivation of LKB1 in these glia results in aberrant mitochondrial energy metabolism and progressive degeneration of axons. Remarkably, such non-cell-autonomous axon degeneration is not preceded by changes of OLG structure and myelination, indicating that it occurs secondary to glial metabolic perturbation. These discoveries lead us to hypothesize that LKB1 and its downstream metabolic effectors, most notably those regulating mitochondrial metabolism in OLGs, are integral to the trophic support mechanisms for axons. Using manipulation of LKB1 signaling as an experimental tool to change glial metabolism with no impact on other biological outputs of OLGs, here we implement a multidisciplinary approach that will afford us the unique opportunity to pinpoint metabolic alterations in OLGs that disrupt the support of axons. In this context we will also investigate whether axons degenerate as a consequence of energetic deprivation, or metabolic poisoining. Together, this will provide valuable data to elucidate which downstream components of the LKB1-dependent metabolic signaling network in OLGs are fundamentally important for axon integrity. The proposed efforts may open the door to the identification of unexpected metabolic components in OLGs that are essential for axon support. Manipulation of these components will have the potential to promote axon integrity in neurodegenerative diseases. Because glial and metabolic abnormalities associated with axon degeneration can be observed in many neurodegenerative conditions, this approach has the potential for wide-ranging therapeutic impact.

关于髓鞘神经胶质如何促进长期健康的基本神经科学问题 轴突很广泛。轴突是神经回路特别脆弱的组成部分 在许多令人衰弱的神经退行性疾病的早期阶段不可逆地损坏 例如多发性硬化症和阿尔茨海默氏病。神经胶质的机制 仅了解轴突损伤的贡献。少突胶质细胞（OLGS） 中枢神经系统的髓质神经胶质，通过不良理解稳定轴突完整性 营养机制。当前的模型表明，神经胶质代谢对于这种支持至关重要 功能，OLG和轴突之间的代谢交换破坏，或代谢定义 OLG可能导致轴突变性。为了支持，我们令人兴奋地发现LKB1 （肝激酶B1）信号通路是OLG中的重要代谢调节剂，而失活 这些神经胶质中的LKB1导致线粒体能量代谢异常 轴突的变性。值得注意的是，这种非细胞自主轴突变性不是 在OLG结构和髓鞘化的变化之前，表明它发生于 神经胶质代谢扰动。这些发现使我们假设LKB1及其 下游代谢作用，最值得注意的是那些调节线粒体代谢的人 OLG是轴突的营养支撑机制不可或缺的。使用LKB1的操纵 信号传导是改变神经胶质代谢的实验工具，对其他生物学没有影响 OLGS的输出，在这里我们实施了一种多学科的方法，该方法将为我们提供独特的 在OLGS中查明破坏轴突支撑的OLG中的代谢改变的机会。在这个 上下文我们还将调查轴突是否由于能源而退化 剥夺或代谢性倾斜。一起，这将提供有价值的数据来阐明哪些 OLG中LKB1依赖性代谢信号网络的下游成分是 对于轴突完整性至关重要。拟议的努力可能打开了 鉴定OLG中意外代谢成分对于轴突支持至关重要。 操纵这些组件将有可能促进轴突完整性 神经退行性疾病。因为与轴突有关的神经胶质和代谢异常 在许多神经退行性条件下都可以观察到变性，这种方法具有 大范围治疗的潜力。