How Does Actin Disassembly Drive Myelin Wrapping?

肌动蛋白分解如何驱动髓磷脂包裹？

• 批准号: 10302789
• 负责人: John B Zuchero
• 金额: $ 5.79万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10302789
• 关键词: Actins; Axon; Chronic; Cytoskeleton; Data; Disease; Foundations; Future; Genetic; Goals; Growth Cones; Impairment; Injury; Knowledge; Membrane; Methods; Microfilaments; Microscopy; Modeling; Multiple Sclerosis; Multiple Sclerosis Lesions; Myelin; Neuraxis; Neurons; Oligodendroglia; Patients; Primary Cell Cultures; Process; Research; Role; Techniques; Testing; Vertebrates; base; cell motility; disability; in vivo; innovation; live cell imaging; myelination; nervous system development; nervous system disorder; neuronal growth; neurotransmission; remyelination; tool; translational study

PROJECT SUMMARY/ABSTRACT Myelin—the electrical insulator around neuronal axons—is essential in vertebrates for rapid nerve signaling, and its loss in diseases like multiple sclerosis and following injury causes severe disability in patients. In the central nervous system, oligodendrocytes build myelin by first extending their membrane processes to ensheath axons, then wrapping spirally around the axon while compacting their membranes to become electrically insulating. In chronic multiple sclerosis lesions, oligodendrocytes ensheath axons but fail to wrap, suggesting that wrapping is a rate-limiting step for remyelination. To ultimately understand why remyelination fails in multiple sclerosis, we first aim to understand the mechanism by which myelin wraps normally. It was long hypothesized that the assembly of actin filaments provides the force required to drive wrapping, like the lamellipodium of a motile cell or a neuronal growth cone. However, we and others recently discovered that the dramatic disassembly of the oligodendrocyte actin cytoskeleton is required for wrapping. This finding was completely unexpected and suggests two models for wrapping. Cycles of actin disassembly and reassembly could be required to “ratchet” the oligodendrocyte membrane forward. In contrast, based on our preliminary data, we propose that actin disassembly acts as a “trigger” to initiate actin-independent wrapping and that the major role of actin disassembly is to allow myelin to compact. To test these models, we are using a suite of innovative approaches including first-in-class genetic tools we created to experimentally induce actin disassembly (DeActs) or block actin disassembly (StablActs) in oligodendrocytes during wrapping in vivo, advanced microscopy techniques to resolve myelin in vivo, and live cell imaging of oligodendrocytes in culture. Our preliminary data demonstrate: (1) actin filaments disassemble in oligodendrocytes prior to wrapping, (2) experimentally inducing actin disassembly specifically in oligodendrocytes in vivo increases myelin wrapping, and (3) experimentally blocking actin disassembly impairs myelin membrane compaction in a culture model of myelination. These data support the “trigger” model of myelin wrapping, laying the foundation for future translational studies to test whether this actin disassembly-based mechanism is recapitulated or perturbed during remyelination. By defining the role of actin disassembly in myelin wrapping and compaction, this project will open up new research directions towards understanding myelin formation, plasticity, and disease in the central nervous system.

项目摘要/摘要 髓磷脂 - 神经元轴突周围的电绝缘体 - 在脊椎动物中至关重要的，对于快速神经信号传导， 及其在多发性硬化症等疾病中的丧失和受伤后导致患者严重残疾。在 中枢神经系统，少突胶质细胞首先将其膜过程扩展到 围绕轴突，然后在轴突上精神上包裹，同时压实其机制 电绝缘。在慢性多发性硬化病变中，少突胶质细胞围绕轴突，但无法包裹， 表明包装是延期延期的限制步骤。最终理解为什么再髓 在多发性硬化症中失败，我们首先要了解髓磷脂正常包裹的机制。是 长期假设肌动蛋白丝的组装提供了驱动包裹所需的力，例如 母细胞或神经元生长锥的薄片。但是，我们和其他人最近发现 包装需要少突胶质细胞肌动蛋白细胞骨架的戏剧性拆卸。这个发现是 完全出乎意料，并建议包装两个模型。肌动蛋白拆卸和重新组装的周期 可能需要“棘轮”少突胶质细胞膜前进。相反，基于我们的初步 数据，我们建议肌动蛋白拆卸是启动与肌动蛋白无关的包装的“触发”，并且 肌动蛋白拆卸的主要作用是使髓磷脂紧凑。为了测试这些模型，我们使用了一套 创新方法包括我们创建的一类遗传工具，以实验诱导肌动蛋白 在体内包装期间，拆卸（脱）或阻止肌动蛋白拆卸（稳定）（稳定） 先进的显微镜技术可以在体内解决髓磷脂，并在培养中少突胶质细胞的活细胞成像。 我们的初步数据证明了：（1）肌动蛋白丝包装之前的少突胶质细胞中拆卸，（2） 实验诱导的肌动蛋白在体内特有在少突胶质细胞中脱组合会增加髓磷脂包裹， （3）实验阻断肌动蛋白拆卸会损害髓鞘膜的压实 髓鞘。这些数据支持髓磷脂包装的“触发”模型，为未来奠定了基础 转化研究以测试这种基于肌动蛋白的基于肌动蛋白的机制是概括或扰动的 在再髓时。通过定义肌动蛋白拆卸在髓鞘包装和压实中的作用，该项目 将为了解髓磷脂形成，可塑性和疾病的新研究方向 中枢神经系统。