Energizing and Protecting Axons Through Metabolic Coupling to Schwann Cells

轴突及其相关的胶质细胞(雪旺细胞和少突胶质细胞)构成神经元的最大部分。 网络。轴突需要保持旺盛的精力，并且容易受到各种有害刺激的影响。 轴突功能障碍和病理性轴突变性(PAxD)已成为一种主要的病理生理机制 许多神经退行性疾病的司机。因此，治疗的中心焦点是开发治疗方法。 为保护轴突而量身定做。这种疗法的先决条件是更好地理解自主和非自主性的 调节导致pAxD的过程的细胞自主分子机制。物理断开 来自神经元细胞体的轴突是一个广泛使用的实验平台，它极大地改善了我们的 过去二十年来对这些进程的理解。主要研究外周神经系统 在脊椎动物中，这种模式会触发雪旺细胞的早期损伤反应，然后是快速和刻板的反应 轴突解体(沃勒氏变性)。现在已经知道轴突的解体是由一种 保守的自动破坏计划，通过迅速消耗代谢来耗尽轴突ATP内容 未连接轴突中的辅因子NAD。重要的是，最近的研究表明轴突具有指导作用。 损伤轴突生存的生物能量学。鉴于神经退行性疾病广泛相关 轴突生物能量缺陷，这些发现表明轴突生物能量的下降占据了 在通向pAxD的通路中的中心位置。为了支持这一点，我们最近有了一个令人兴奋的发现 雪旺细胞在轴突损伤后早期转换能量代谢以对抗结构破坏 可能是通过增加糖酵解终末产物的供应(轴突-神经胶质代谢偶联)。 此外，我们发现，雪旺细胞中代谢损伤适应的操纵加速或 延缓急性和亚急性pAxD模型中扰动轴突的退化。这是第一次， 展示了一种控制受损轴突命运的非细胞自主的能量机制。第一个目标 试图确定所提出的代谢耦合机制是否抵消了 通过增加支持轴突三磷酸腺苷的神经胶质甘露糖酸盐的供应，损伤轴突的减少 制作。下一个目标是扩大对代谢偶联的关键成分的识别 对支持受损轴突至关重要的途径，重点是轴突线粒体。最终目标是 在一个医源性疾病模型中检查代谢偶联的操作如何影响pAxD。 亚急性轴突扰动。总体而言，这项工作有可能引入一种范式转变，从 轴突保护的神经元中心观点。拟议的努力可能会为未来的发展打开大门 考虑轴突和神经胶质生物能量学之间的关系的新的治疗方法 对抗神经退行性疾病中的pAxD。 。

Axons and their associated glia (Schwann cells and oligodendrocytes) form the largest part of the neuronal network. Axons are challening to maintain energetically and are vulnerable to a wide spectrum of noxious stimuli. Dysfunction of axons and pathological axon degeneration (pAxD) have emerged as a major pathophysiological driver in many neurodegenerative diseases. Consequently, a central therapeutic focus is to develop approaches tailored to protect axons. A prerequisite for such therapies is a better understanding of the autonomous and non- cell autonomous molecular mechanisms that regulate the processes leading to pAxD. Physical disconnection of the axon from the neuronal cell body is a widely-used experimental platform that has dramatically improved our understanding of these processes over the last two decades. Primarily studied in the peripheral nervous system of vertebrates, this paradigm triggers early injury responses in Schwann cells followed by rapid and stereotyped disintegration of axons (Wallerian degeneration). It is now known that axon disintegration is evoked by a conserved auto-destruction program that exhausts axonal ATP content through rapid depletion of the metabolic cofactor NAD+ in disconnected axons. Importantly, recent studies indicate an instructive role of axonal bioenergetics for the survival of injured axons. Given that neurodegenerative diseases are broadly associated with axonal bioenergetic defects, these findings suggest that the decline of axonal bioenergetics occupies a central position in the pathway leading to pAxD. In support of this, we recently made the exciting discovery that Schwann cells convert their energy metabolism early upon axon injury to antagonize the structural breakdown of injured axons, likely through the increased supply of glycolytic end-products (axon-glia metabolic coupling). Furthermore, we found that the manipulation of the metabolic injury adaptation in Schwann cells accelerates or delays the degeneration of perturbed axons in acute and subacute pAxD models. For the first time, this demonstrates a non-cell-autonomous energetic mechanism that controls the fate of injured axons. The first aim of this proposal attempts to determine if the suggested metabolic coupling mechanism counteracts the energetic decline of injured axons through the enhanced supply of glial manocarboxylates that support axonal ATP production. The next objective extends the identification of the key components of the metabolic coupling pathway critical for the support of injured axons with an emphasis on axonal mitochondria. The final goal intends to examine as to how manipulation of metabolic coupling influences pAxD in an iatrogenic disease model of subacute axon pertubation. Collectively, this work has the potential to introduce a paradigm shift away from neuron-centric views of axon protection. The proposed efforts may open the door for the future development of novel therapeutic approaches taking into account the relationship between axonal and glial bioenergetics to combat pAxD in neurodegenerative disorders. .