The regulation of axon degeneration by SARM1

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The aim of this Industrial Partnership is to understand a preventable and widely-occurring mechanism of axon degeneration, known as Wallerian degeneration, underpinning a rapidly increasing interest in drug development. When activated by nerve injury, blocking Wallerian degeneration can rescue axons for several weeks. When activated by disrupting one specific protein, we recently showed that blocking it rescues axons indefinitely. Animal and cell culture studies indicate the Wallerian degeneration mechanism contributes widely to disease so it has become an important goal in the Pharmaceutical industry. Together with our industrial partner, AstraZeneca, we will focus on crucial step in the pathway generating new basic knowledge that will support future drug development.Axons are the long fibres that connect one nerve cell with another, relaying electrical information around our nervous system. They are essential for many normal body functions, not only those we typically associate with nervous system such as thinking, memory, pain and movement, but also for vision, hearing, gut function, bladder control and breathing. In short, without fully functional axons there is no normal life.Unfortunately, axons are the most vulnerable parts of our nerve cells. Many of them are very long, up to one meter compared to typical cellular dimensions of a fraction of a millimeter. Other axons are highly branched, posing a significant challenge for the far smaller cell body to support it. Like any remote structure dependent on central support, axons die first when things go wrong, for example in ageing, injury and disease.Our research opened up an entirely new field in understanding why axons degenerate and how we can prevent it. We identified the first gene known to preserve injured axons and showed that it also protects axons that are compromised in other ways without physical injury. Stemming from this finding, disruption of other genes has been found to block Wallerian degeneration too. This project focusses on one of them, SARM1, a protein required for axons to undergo Wallerian degeneration. In some circumstances, blocking SARM1 confers lifelong rescue of axons.SARM1 has become an area of considerable interest to the Pharma industry, including to our industrial partner AstraZeneca, following identification of an enzyme activity associated with it. In order to maximise the chance of success, it is vital to understand SARM1 function more than we currently do. In particular, we needto understand how it is regulated and the molecular consequences of its activation that lead to axon death. Our group has already made significant progress by identifying steps in the Wallerian degeneration mechanism that precede SARM1 activation. Here we present new hypotheses regarding these next steps together with strategies to test them.These studies should identify new strategies to block SARM1 activation and rescue axons from degeneration. Thus, our industrial partner AstraZeneca is co-sponsoring this proposal and will contribute significant additional expertise in molecular neuroscience, chemistry and mass spectrometry. Together with our long-term collaborators Giuseppe Orsomando and colleagues, experts in NAD metabolism, we make a highly effective team able to drive this important topic forward and underpin future drug development.