The regulation of axon degeneration by SARM1

这一工业伙伴关系的目的是了解一种可预防的、广泛发生的轴突变性机制，即沃勒变性，这支持了人们对药物开发迅速增长的兴趣。当被神经损伤激活时，阻止沃勒变性可以挽救轴突数周。当通过破坏一种特定的蛋白质来激活时，我们最近表明，阻止它可以无限期地拯救轴突。动物和细胞培养研究表明，沃勒退变机制对疾病有广泛的贡献，因此已成为制药行业的一个重要目标。我们将与我们的工业合作伙伴阿斯利康一起，专注于产生新的基础知识的途径中的关键一步，这些知识将支持未来的药物开发。轴突是连接一个神经细胞和另一个神经细胞的长纤维，在我们的神经系统周围传递电子信息。它们对许多正常的身体功能是必不可少的，不仅是那些我们通常与神经系统联系在一起的功能，如思维、记忆、疼痛和运动，而且对视觉、听力、肠道功能、膀胱控制和呼吸也是如此。简而言之，没有功能齐全的轴突就没有正常的生命。不幸的是，轴突是我们神经细胞中最脆弱的部分。它们中的许多都很长，长达一米，而典型的细胞尺寸只有一毫米的零点几。其他轴突是高度分枝的，这对小得多的细胞体支撑它构成了巨大的挑战。就像任何依赖中枢支持的远程结构一样，轴突在出现问题时首先死亡，例如在衰老、损伤和疾病中。我们的研究在理解轴突退化以及如何防止它方面开辟了一个全新的领域。我们确定了第一个已知的保护受损轴突的基因，并表明它也可以保护以其他方式受损的轴突，而不会造成身体损伤。由于这一发现，其他基因的中断也被发现可以阻止沃勒式退化。这个项目的重点是其中之一，Sarm1，一种轴突经历沃勒式退化所需的蛋白质。在某些情况下，阻断Sarm1可以终生挽救轴突。在确定了与SARM1相关的一种酶活性后，SARM1已经成为制药行业的一个相当感兴趣的领域，包括我们的工业合作伙伴阿斯利康。为了最大化成功的机会，比我们现在更多地了解Sarm1的功能是至关重要的。特别是，我们需要了解它是如何被调控的，以及它的激活导致轴突死亡的分子后果。我们的研究小组已经通过确定在Sarm1激活之前的沃勒退变机制中的步骤，已经取得了重大进展。在这里，我们提出了关于这些后续步骤的新假设以及测试它们的策略。这些研究应该确定新的策略来阻止Sarm1的激活和拯救轴突的退化。因此，我们的工业合作伙伴阿斯利康将共同发起这项提议，并将在分子神经科学、化学和质谱学方面贡献大量额外的专业知识。与我们的长期合作者朱塞佩·奥索曼多及其同事、NAD新陈代谢专家一起，我们组成了一个高效的团队，能够推动这一重要课题向前发展，并为未来的药物开发奠定基础。

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.