Spatio-temporal imaging of calcium in degenerating nerves

轴突是将大脑、脊髓和周围神经系统内的神经元连接在一起的长过程，使神经元能够快速相互交流。它们是巨大的结构，在人类体内可达1米长，例如使人类运动神经元成为人体内最大的单个细胞。自然而然地，对于如此巨大的结构，维护轴突存在重大的后勤问题。未能做到这一点是许多人类神经疾病的原因，不仅是那些有直接轴突损伤的疾病，如脊髓损伤，而且还有许多疾病是遗传性的，如运动神经元病，或后天获得的，如暴露于神经毒素。我们开始理解，在这些看似不相关的情况下，轴突死亡的方式是相似的。然而，我们还没有完全了解这一机制是什么。钠和钾等无机离子在动作电位的传递中起着重要作用，动作电位是信息沿着轴突从一端快速传递到另一端的方式。然而，另一种无机离子钙在轴突中扮演着截然不同但同样关键的角色。钙通常从包括神经元在内的所有细胞中排出，因为细胞内高水平的钙是极其危险的。它也被注入到细胞内的特定存储中，包括轴突内部，在那里它可以被释放，并被用来发出特定事件和过程的信号，以便细胞或轴突可以做出相应的反应。我们有一些初步数据表明，这些钙库的钙释放发生在轴突受伤之后，但在轴突真正退化之前很久。当我们在存在保护受损轴突不退化的基因突变的情况下重复这些实验时，钙的重新分配也被阻止了。这两个事件之间可能的因果联系需要通过适当的实验来确定。例如，如果从内部存储器释放的钙是导致轴突退化的信号机制的一部分，那么人们会认为通过另一种方法(例如，通过添加适当的药物)导致从细胞内存储器释放钙将具有类似的效果。我们将进行一系列实验来测试这种因果联系，如果我们找到了它，就会确定它可能被如何利用。短期内，我们的目标是更好地了解轴突死亡的基本机制。这是一个非常重要的问题，因为到目前为止，轴突构成了大多数神经元的最大部分，而且因为它们对神经元的功能是必不可少的，而且在大多数情况下，如果它们丢失了，就不能被替换。从长远来看，了解这一过程应该会导致治疗甚至预防广泛的神经退行性疾病的新方法。

Axons are the long processes that link neurons together within our brain, spinal cord and peripheral nervous system, allowing neurons to communicate rapidly with one another. They are huge structures, up to 1 metre long in man, making human motor neurons, for example, the largest single cell within the human body. Naturally with such huge structures, there are significant logistical problems in maintaining axons. Failure to do so is the cause of a number of human neurological disorders, not only those where there is direct axonal injury such as spinal injury, but also many where the disorder is inherited such as motor neuron disease, or acquired such as exposure to neurotoxins. We are beginning to understand that the way in which axons die is similar in each of these seemingly unrelated circumstances. However, we do not yet fully understand what that mechanism is. Inorganic ions such as sodium and potassium play important roles in the transmission of the action potential, the means by which information passes rapidly along an axon from one end to another. However, another inorganic ion, calcium, plays a rather different but equally critical role in axons. Calcium is normally pumped out of all cells, including neurons, because high levels of calcium inside the cell are extremely dangerous. It is also pumped into specific stores within cells, including inside the axon, from where it may be released and used to signal certain events and processes so that the cell or axon can respond accordingly. We have some preliminary data suggesting that release of calcium from such stores occurs after an axon is injured, but long before the axon actually degenerates. When we repeated these experiments in the presence of a genetic mutation that protects injured axons from degenerating, the redistribution of calcium was also blocked. The possible causative link between these two events needs to be established by appropriate experiments. For example, if calcium release from the internal stores is part of the signalling mechanism that causes the axon to degenerate, then one would expect that causing calcium to be released from intracellular stores by another method (e.g., by adding an appropriate drug) would have a similar effect. We will carry out a series of experiments to test for such a causative link, and if we find it, to determine how it might be exploited. In the short term our aim is to understand better fundamental mechanisms of axon death. This is a very important issue because axons make up by far the largest part of most neurons and because they are essential for the function of that neuron and for the most part cannot be replaced if they are lost. In the longer term, understanding this process should lead to new ways to treat, or even prevent, a wide spectrum of neurodegenerative conditions.