Elucidating the interlinked roles of spastin and protrudin in axonal degeneration and regeneration

阐明 spastin 和 protrudin 在轴突变性和再生中的相互关联的作用

• 批准号: MR/V028677/1
• 负责人: Evan Reid
• 金额: $ 68.79万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV028677%2F1
• 关键词: Elucidating; interlinked; roles; spastin; protrudin

Axons are long threadlike parts of nerve cells (neurons) and they conduct electrical signals from one neuron to another. Degeneration of axons contributes to both rare and common neurological conditions, while axons in the brain and spinal cord have a poor capacity to regrow after injury, explaining the devastating effects of, for example, paralysis after spinal cord injury. This means that it is important that we understand in molecular detail what axons need to stay healthy, as this might reveal strategies to prevent axonal degeneration and promote regrowth after injury.This project examines the molecular biology of two proteins related, spastin and protrudin, that work together in cells, and which have been implicated respectively in axon degeneration and regrowth. Neurons lacking sufficient amounts of spastin for a long period develop axonal degeneration and this underlies one cause of a condition called hereditary spastic paraplegia, in which affected people become paralysed. In contrast, neurons in which the amounts of protrudin have been experimentally increased develop a better capacity to regrow after injury. In our recent work in non-neuronal cells, we have found that one function of spastin is to inhibit protrudin. In this project, we will test whether this same relationship between the proteins exists in nerve cells, and if so will determine in detail how spastin inhibits protrudin. As decreasing the activity of spastin enhances the activity of protrudin, we will ask whether this increases the potential for axon regrowth, which could potentially represent a treatment strategy after nerve damage in the brain or spinal cord. Finally, we will test whether over-activation of protrudin is responsible for some of the pathological effects of lack of spastin. If this is that case it would suggesting that blocking the effects of protrudin could be a treatment for hereditary spastic paraplegia. Overall, this project will enhance our understanding of the fundamental biology that underpins axon health and potential for regrowth after injury, could uncover unsuspected links between the mechanisms of axonal degeneration and regeneration, as well as potentially identifying new treatment strategies for neuro-degenerative conditions and nerve injury in the brain and spinal cord.

轴突是神经细胞(神经元)的长线状部分，它们将电信号从一个神经元传导到另一个神经元。轴突的退化导致罕见和常见的神经疾病，而大脑和脊髓中的轴突在损伤后再生的能力很差，这解释了例如脊髓损伤后瘫痪的破坏性影响。这意味着重要的是我们要从分子细节上了解轴突需要什么才能保持健康，因为这可能揭示防止轴突退化和促进损伤后再生的策略。这个项目研究了两种相关蛋白质的分子生物学，这两种蛋白质在细胞中共同作用，分别与轴突退化和再生有关。长期缺乏足够数量的痉挛蛋白的神经元会发展成轴突退化，这是遗传性痉挛截瘫的一个原因，在这种情况下，受影响的人会瘫痪。相比之下，实验中突起蛋白含量增加的神经元在损伤后再生能力更强。在我们最近对非神经细胞的研究中，我们发现spastin的一个功能是抑制突起蛋白。在这个项目中，我们将测试神经细胞中是否存在这种蛋白质之间的相同关系，如果存在，将详细确定spastin如何抑制突起蛋白。随着spastin活性的降低增强了proproudin的活性，我们将询问这是否增加了轴突再生的潜力，这可能代表着大脑或脊髓神经损伤后的一种治疗策略。最后，我们将测试突起蛋白的过度激活是否与痉挛蛋白缺乏的一些病理效应有关。如果是这样的话，这将表明阻断突出素的作用可能是治疗遗传性痉挛截瘫的一种方法。总体而言，该项目将加强我们对支撑轴突健康和损伤后再生潜力的基础生物学的理解，可能揭示轴突退化和再生机制之间的意外联系，以及潜在地确定神经退行性疾病和大脑和脊髓神经损伤的新治疗策略。