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递到另一个神经元。轴突的退化会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受伤后再生能力差，这解释了脊髓损伤后瘫痪等毁灭性后果。这意味着我们了解轴突保持健康所需的分子细节是很重要的，因为这可能揭示防止轴突退化和促进损伤后再生的策略。该项目研究了两种相关蛋白的分子生物学，spastin和proudin，它们在细胞中一起工作，分别与轴突退化和再生有关。长期缺乏足够量的痉挛素的神经元会发生轴突变性，这是导致遗传性痉挛性截瘫的原因之一，患者会瘫痪。相反，在实验中突起蛋白数量增加的神经元在损伤后具有更好的再生能力。在我们最近对非神经元细胞的研究中，我们发现spastin的一个功能是抑制突起蛋白。在这个项目中，我们将测试神经细胞中蛋白质之间是否存在同样的关系，如果存在，将详细确定spastin如何抑制突起蛋白。由于减少痉挛蛋白的活性可以增强突蛋白的活性，我们将询问这是否会增加轴突再生的潜力，这可能是脑或脊髓神经损伤后的一种治疗策略。最后，我们将测试伸肌蛋白的过度激活是否导致了痉挛蛋白缺乏的一些病理影响。如果是这样的话，那就表明阻断突肽的作用可能是一种治疗遗传性痉挛性截瘫的方法。总的来说，这个项目将增强我们对基础生物学的理解，支持轴突健康和损伤后再生的潜力，可以揭示轴突退化和再生机制之间的未知联系，以及潜在地确定神经退行性疾病和脑和脊髓神经损伤的新治疗策略。

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.