Grant: CIHR Fellowship

Neurons have long processes that connect the brain and spinal cord to the muscles and rest of the body. These long processes, termed axons, are surrounded by an insulating layer known as myelin. When myelin is lost in diseases like multiple sclerosis (MS), traumatic injuries or in genetic disorders, like an electrical wire being stripped of its insulation, the axon struggles to send signals and may even degenerate. The degeneration of axons is the cause of progressive disability in diseases like MS. Therapies that mitigate their loss should be effective in reducing disability. However, the reasons why axons degenerate following myelin loss (termed demyelination) are unclear. The goal of this proposal is to identify the factors that damage neurons and their axons in demyelinating disease, and to identify ways to promote their survival. To induce demyelination, I will selectively inactivate the cells which produce myelin in adult mice. This a more precise way of inducing demyelination than previous experimental approaches which used toxins or activated the immune system, both of which can directly damage neurons. I will use this model to determine if demyelinated axons eventually require newly regenerated myelin and if overactive immunity, like that present in MS lesions, preferentially damages demyelinated axons. I will then examine all the messengers within a neuron that coordinates their response to demyelination. By examining these messengers, our goal is to identify specific changes that are necessary for axonal survival following demyelination. These specific changes will then be disrupted using new gene editing techniques to see what effect they have on the axon following demyelination. Together, these experiments will provide new insights in to the relative vulnerability of demyelinated axons, and whether their survival can be boosted by targeting their natural adaptive mechanisms.