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.

关于髓鞘神经胶质细胞如何促进长期健康的基本神经科学问题 轴突的研究还很不足。轴突是神经回路中特别脆弱的组成部分 在许多使人衰弱的神经退行性疾病的早期阶段受到不可逆转的损害 例如多发性硬化症和阿尔茨海默病。胶质细胞的潜在机制 对轴突损伤的影响目前还知之甚少。少突胶质细胞 (OLG) 中枢神经系统的髓鞘神经胶质细胞，通过知之甚少的方式稳定轴突完整性 营养机制。目前的模型表明神经胶质代谢对于这种支持至关重要 功能，并扰乱 OLG 和轴突之间的代谢交换，或代谢缺陷 OLGs 可能导致轴突变性。作为支持，我们做出了令人兴奋的发现，即 LKB1 （肝激酶 B1）信号通路是 OLG 中至关重要的代谢调节因子，其失活 这些神经胶质细胞中 LKB1 的缺失导致线粒体能量代谢异常和进行性进展 轴突退化。值得注意的是，这种非细胞自主的轴突变性并不是 先于 OLG 结构和髓鞘形成的变化，表明它继发于 神经胶质代谢扰动。这些发现使我们推测 LKB1 及其 下游代谢效应器，最显着的是那些调节线粒体代谢的效应器 OLG 是轴突营养支持机制不可或缺的一部分。使用 LKB1 的操作 信号传导作为改变神经胶质代谢的实验工具，而不影响其他生物 OLG 的产出，在这里我们实施多学科方法，这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变化。在这个 我们还将研究轴突是否因能量消耗而退化 剥夺或代谢中毒。总之，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组件是 对于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 中意想不到的代谢成分，这些成分对轴突支持至关重要。 对这些成分的操纵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相关 在许多神经退行性疾病中都可以观察到退行性变，这种方法具有 具有广泛治疗影响的潜力。