Elucidating the trophic support of long axons by metabolic signaling in oligodendrocytes

髓鞘胶质细胞如何促进Long的健康的基础神经科学问题 轴突的研究严重不足。轴突是神经回路中特别脆弱的组成部分 在许多衰弱的神经退行性疾病的早期阶段，它们受到不可逆转的损害 例如多发性硬化症和阿尔茨海默氏症。神经胶质细胞的潜在机制 对轴突损伤的作用仅是一般的理解。少突胶质细胞(OLG) 中枢神经系统的髓鞘胶质细胞，稳定轴突的完整性，知之甚少 营养机制。目前的模型表明，神经胶质代谢对这种支持至关重要。 功能，并扰乱OLG和轴突之间的代谢交换，或 OLG可导致轴突变性。作为支持，我们发现了令人兴奋的LKB1 (肝脏激酶B1)信号通路是OLG中重要的代谢调节因子，其失活 在这些胶质细胞中LKB1的表达导致线粒体能量代谢的异常和进行性 轴突变性。值得注意的是，这种非细胞自主的轴突变性并不 之前有OLG结构和髓鞘的变化，表明它发生在继发于 神经胶质代谢紊乱。这些发现使我们假设LKB1及其 下游代谢效应物，最著名的是调节线粒体代谢的那些 OLG是轴突营养支持机制不可或缺的一部分。使用LKB1的操作 信号作为一种实验工具改变神经胶质代谢而不影响其他生物 在这里，我们实施了一种多学科的方法，将为我们提供独特的 有机会准确定位破坏轴突支持的OLG的代谢变化。在这 背景我们还将调查轴突退化是否是能量过高的结果 剥夺，或代谢紊乱。总而言之，这将提供有价值的数据来阐明 OLG中依赖LKB1的代谢信号网络的下游组件为 对轴突的完整性至关重要。拟议的努力可能会打开通往 确定OLG中对轴突支持至关重要的意想不到的代谢成分。 这些组件的操作将有可能促进轴突的完整性 神经退行性疾病。因为与轴突相关的神经胶质和代谢异常 在许多神经退行性疾病中都可以观察到退变，这种方法具有 有可能产生广泛的治疗影响。

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.