30 years of programmed axon death

Introduction to: Coleman and Höke (2020)

By Professor Michael Coleman

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Picture these two points in neuroscience history:

London, 1850 – Augustus Waller notices that frog nerves degenerate when they are injured. It doesn’t sound so groundbreaking now, but this was an age long before synapses or axonal transport had even been thought of. Even the existence of discrete neurons in the brain was still hotly disputed. Waller’s observation changed a lot. He concluded that cell bodies ‘nourish’ the nerve and the process he observed became known as Wallerian degeneration.

Oxford, 1989 – Hugh Perry and Michael Brown are routinely using Waller’s method to make mouse nerves degenerate, enabling them to study their subsequent regeneration. But the injured nerves in their apparently normal mice did not degenerate.

What could be the explanation? A difference between frogs and mice? Other investigators had already reported ‘normal’ Wallerian degeneration in mice. Perhaps they hadn’t cut the nerves properly? They repeated the experiment with the same outcome. However, nerves from other mice degenerated as expected. Something was different about these mice.

Perry and Brown were about to initiate an entirely new research field. Programmed cell death was fresh in everyone’s mind as the big new breakthrough. Could axons also undergo a programmed death mechanism that that somehow ‘failed’ in these mice?  If so, what was that mechanism and was it relevant to disease?

Using classical Mendelian genetics, Perry and Brown showed that prolonged axon survival was inherited and semi-dominant. They used tissue transplants to show it was a property of axons, not of other nerve cell types. Then, together with Mary Lyon, famous for her discovery of X chromosome inactivation, they began tracking down the protective gene.

Within 30 years, there would be a druggable, molecular pathway targeted by Pharma for therapies in a range of axonal disorders. Human mutations would be known that activate this pathway, and these are associated with lethality and rare disease. Permanent rescue of axons, at least in some circumstances, would become possible.

To find out how, read our review in Nature Reviews Neuroscience: Programmed axon degeneration: from mouse to mechanism to medicine.

Ahmet Höke and I were young postdocs with Jack Griffin and Hugh Perry when we first learned about these remarkable mice. Over three decades we have had the privilege of experiencing progress that no-one could have imagined back then. It is a fascinating story of a billion years of evolution linking flies with mammals, of newly discovered enzymes metabolising ‘old’ molecules, and of new research made possible by the latest human genomic methods.

Today, research into programmed axon degeneration stands on the brink of clinical application. If the field could go from Mouse to Mechanism to Medicine in 30 years, where will the next 30 take us?