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

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。轴突的变性导致罕见和常见的神经系统疾病，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。这意味着我们必须从分子水平上了解轴突保持健康所需的细节，因为这可能揭示防止轴突变性和促进损伤后再生的策略。本项目研究了两种相关蛋白的分子生物学，即spastin和replodin，它们在细胞中共同作用，分别与轴突变性和再生有关。神经元长期缺乏足够的痉挛素会发展成轴突变性，这是遗传性痉挛性截瘫的原因之一，受影响的人会瘫痪。相比之下，在实验中增加了Escheridin含量的神经元在损伤后再生的能力更好。在我们最近对非神经元细胞的研究中，我们发现spastin的一个功能是抑制pathodin。在这个项目中，我们将测试蛋白质之间是否存在相同的关系在神经细胞中，如果是这样的话，将详细确定痉挛素如何抑制神经元蛋白。由于降低spastin的活性增强了spastin的活性，我们将询问这是否增加了轴突再生的潜力，这可能代表了大脑或脊髓神经损伤后的治疗策略。最后，我们将测试是否过度激活的spastin是负责缺乏痉挛的一些病理影响。如果是这样的话，这将表明阻断Escheridin的作用可能是治疗遗传性痉挛性截瘫的一种方法。总的来说，该项目将增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，可以揭示轴突变性和再生机制之间的未知联系，以及可能确定新的治疗策略神经退行性疾病和脑和脊髓神经损伤。

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.