A survival factor for axons: Role in disease and downstream mechanism

Lead Research Organisation: Babraham Institute
Department Name: UNLISTED


Our nervous system cannot function without axons, the long 'wires' conducting electrical signals from one nerve cell (neuron) to another. Even if other parts of the neuron (the cell body and dendrites) survive, a neuron without an axon is functionally dead. Axons are very vulnerable because of their immense length (up to one metre in man) and their need to deliver essential components from cell bodies to all locations along their lengths using a sophisticated process known as 'axonal transport'. Consequently, axon degeneration makes critical contributions to symptoms in many neurodegenerative conditions, including multiple sclerosis, glaucoma, diabetic neuropathy, motor neuron disease and Alzheimer's disease. Once lost, axons in our brain and spinal cord do not regenerate so it is essential to preserve them in ageing and disease. We recently identified an enzyme (Nmnat2) as an axon survival factor using a neuronal culture system. We propose that failure to deliver Nmnat2 could be responsible for axon death in diseases where axonal transport fails. This is based on experiments where substituting with a similar but longer-lasting enzyme named WldS increases axon survival and alleviates disease. WldS is not present in people whereas Nmnat2 is, which makes this new development particularly exciting. Because we can now regulate the degenerative process by manipulating a single molecule that humans do have, we can make rapid progress in understanding this type of degeneration and working out the best way to block it pharmacologically. To get the full picture, we also need to study this process in the context of a mammalian nervous system and its roles in neurodegenerative disorders. We will genetically modify mice to block or reduce the production of Nmnat2 in neurons. When its production stops altogether we expect that axons will die through a mechanism called 'Wallerian-like degeneration', a pathway we have studied for many years and can test for using the WldS gene. When production of the proposed survival factor is reduced by around 50%, we expect that axons may initially survive but become more susceptible to other stresses such as neurotoxins, physical pressure, inherited defects that 'clog up' our axons and possibly even normal ageing. By testing whether axonal Nmnat2 levels are reduced in axonal transport disorders, and whether the degree of reduction is related to the severity of the disease, we aim to understand the molecular steps leading to axon degeneration and ultimately target them therapeutically.


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