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

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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.