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: 9887384
• 负责人: Bogdan Beirowski
• 金额: $ 41.35万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9887384
• 关键词: 5' -AMP-activated protein kinase; Ablation; Adult; Alzheimer' s Disease; Attenuated; Axon; Biological; Caliber; Cessation of life; Data; Defect; Deterioration; Disease; Electrophysiology (science); Energy Metabolism; Etiology; Failure; Fiber; GLC2 protein; Genetic; Glean; Glucose; Health Promotion; Homeostasis; Impairment; Individual; Intoxication; Lead; Life Expectancy; Metabolic; Metabolic Pathway; Metabolism; Microfluidic Microchips; Mitochondria; Modeling; Molecular; Multiple Sclerosis; Mutant Strains Mice; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neuroglia; Neurologic; Oligodendroglia; Optic Nerve; Output; Pathway interactions; Phenotype; 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; 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.

神经科学的基本问题是髓鞘神经胶质细胞如何促进长 轴突的研究还远远不够。轴突是神经回路中特别脆弱的组成部分 在许多衰弱性神经退行性疾病的早期阶段受到不可逆的损伤 如多发性硬化症和老年痴呆症。神经胶质细胞 对轴突损伤的贡献知之甚少。少突胶质细胞 中枢神经系统的髓鞘化胶质细胞，稳定轴突的完整性， 营养机制目前的模型表明，神经胶质细胞的代谢是至关重要的支持 功能，并破坏OLG和轴突之间的代谢交换，或代谢缺陷， OLG可导致轴突变性。作为支持，我们有了令人兴奋的发现， （肝激酶B1）信号通路是OLG中重要的代谢调节因子， 在这些神经胶质细胞中LKB 1的表达导致线粒体能量代谢异常， 轴突的退化。值得注意的是，这种非细胞自主性轴突变性并不是 OLG结构和髓鞘形成的变化，表明它发生继发于 神经胶质代谢紊乱这些发现使我们假设LKB 1及其 下游代谢效应物，最明显的是那些调节线粒体代谢的， OLG是轴突营养支持机制的组成部分。使用LKB 1的操作 信号作为实验工具来改变神经胶质代谢，而不影响其他生物学特性。 OLG的输出，在这里，我们实施多学科的方法，将为我们提供独特的 有机会查明OLG中破坏轴突支持的代谢改变。在这 我们还将研究轴突是否由于能量的过度消耗而退化。 剥夺或代谢中毒。总之，这将提供有价值的数据，以阐明 OLG中LKB1依赖性代谢信号网络的下游组分是 对轴突的完整性至关重要拟议的努力可能会打开大门， 鉴定OLG中对轴突支持至关重要的意外代谢成分。 操纵这些组件将有可能促进轴突的完整性， 神经退行性疾病因为神经胶质和代谢异常与轴突 在许多神经退行性疾病中可以观察到退化，这种方法具有 潜在的广泛的治疗影响。