Energizing and Protecting Axons Through Metabolic Coupling to Schwann Cells

通过与雪旺细胞的代谢耦合来激活和保护轴突

• 批准号: 10279519
• 负责人: Elisabetta Babetto
• 金额: $ 37.61万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10279519
• 关键词: Acute; Affect; Antineoplastic Agents; Axon; Bioenergetics; Biosensor; Cessation of life; Chemotherapy-induced peripheral neuropathy; Citric Acid Cycle; Complex; Coupling; Critical Pathways; Data; Defect; Development; Disease; Disease model; Electron Transport; Energy Metabolism; Energy Supply; Enzymes; Etiology; Event; Failure; Functional disorder; Future; Glycolysis; Goals; Iatrogenic Disease; Image; Injury; Instruction; Measures; Mediating; Metabolic; Mitochondria; Modeling; Molecular; Motor; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurologic; Neurologic Deficit; Neurons; Oligodendroglia; Paclitaxel; Pathologic; Pathway interactions; Patients; Peripheral Nervous System; Physiological; Play; Positioning Attribute; Process; Production; Publishing; Pyruvate; Pyruvate Dehydrogenase Complex; Respiration; Role; Schwann Cells; Signal Transduction; Stereotyping; Stimulus; Structure; Therapeutic; Thinking; Time; Up-Regulation; Vertebrates; Wallerian Degeneration; Work; afferent nerve; axon injury; axonal degeneration; axonopathy; cofactor; combat; deprivation; disability; exhaust; extracellular; improved; in vivo; methyl pyruvate; neuronal cell body; novel; novel therapeutic intervention; personalized approach; programs; pyruvate carrier; respiratory; response to injury; therapeutic target; tool; uptake

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. .

轴突及其相关的神经胶质细胞（雪旺细胞和少突胶质细胞）形成神经元的最大部分。 网络轴突被破坏以维持能量，并且容易受到广泛的有害刺激。 轴突功能障碍和病理性轴突变性（pAxD）已成为主要的病理生理学 许多神经退行性疾病的驱动因素。因此，一个中心的治疗重点是开发方法， 专门用来保护轴突这种疗法的先决条件是更好地理解自主和非自主的， 调节pAxD形成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 在过去的二十年里对这些过程的理解。周围神经系统的研究 在脊椎动物中，这种模式触发了雪旺细胞的早期损伤反应，随后是快速和定型的 轴突解体（沃勒变性）。现在我们知道，轴突解体是由一种 保守的自动破坏程序，通过快速消耗代谢产物来消耗轴突ATP含量， 辅因子NAD+在断开的轴突中。重要的是，最近的研究表明，轴突的指导作用， 生物能量学对于受损轴突的存活。鉴于神经退行性疾病与 对于轴突生物能缺陷，这些发现表明轴突生物能的下降占据了 在通向pAxD的途径中的中心位置。为了支持这一点，我们最近取得了令人兴奋的发现， 施万细胞在轴突损伤后早期转换其能量代谢以对抗结构破坏 损伤的轴突，可能通过增加糖酵解终产物的供应（轴突-神经胶质代谢偶联）。 此外，我们发现，操纵雪旺细胞的代谢损伤适应加速或 延迟急性和亚急性pAxD模型中受干扰轴突的变性。这是第一次， 证明了一种非细胞自主的能量机制，控制受伤轴突的命运。第一个目标 该建议的一部分试图确定所建议的代谢偶联机制是否抵消了能量代谢。 通过增强支持轴突ATP的神经胶质羧基酸的供应而减少受损轴突 生产下一个目标扩展了代谢偶联的关键组分的识别 这是支持受损轴突的关键途径，重点是轴突线粒体。最终目标是 研究代谢偶联的操作如何影响pAxD在医源性疾病模型， 亚急性轴突扰动。总的来说，这项工作有可能引入一种范式转变， 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， 新的治疗方法考虑到轴突和神经胶质生物能量学之间的关系， 在神经退行性疾病中对抗pAxD。 .