Variability in human axon survival

轴突是连接一个神经细胞和另一个神经细胞的长“电线”。它们是我们大脑、脊髓和神经的几乎所有退行性疾病中最先丢失的结构之一。其后果包括疼痛、残疾、记忆力丧失、阿尔茨海默病、运动神经元病和多发性硬化症等疾病的听力和视力。周围神经病是影响中枢神经系统外的神经网络的疾病，通常由糖尿病或癌症化疗的副作用引起，是轴突疾病的一个例子。青光眼是另一种因眼内压力导致视神经中断的疾病。研究轴突变性有两种主要方法。一种是动物或细胞培养模型。这些模型系统为研究带来了重大优势，例如，可以以人类不可能的方式研究潜在的分子机制，并且可以在对人类没有风险的情况下测试药物。然而，这些模型往往不能完全代表相应的人类疾病。它们是有效的，因为我们与其他哺乳动物共享大部分DNA序列和大多数类型的细胞，但总是有一些限制。第二个高度互补的方法是人类遗传学。自从人类基因组首次测序以来，测序和分析人类DNA的方法已经有了显着的改进，这正在彻底改变我们对哪些基因可能导致或导致常见和罕见疾病的理解。然而，最终这些结果是相关的，而不是证明。实验模型系统，如上述，需要扩展这项研究。通过对小鼠、细胞培养和果蝇模型中轴突变性的研究，我们在理解一个重要的轴突变性机制方面取得了实质性进展。疾病的动物模型帮助我们了解它在人类疾病和正常衰老中的潜在作用，这是许多神经退行性疾病的最大风险因素。人类遗传学的发展已经独立地表明，这些模型系统中调节轴突变性的蛋白质在人类疾病中起作用，并产生了更多关于这些蛋白质在人群中如何不同的数据。接下来的重要步骤是了解这些蛋白质在人类群体中的变异如何影响正常的蛋白质功能，因此我们将在动物或细胞培养模型中进行类似的改变，以测试是否出现相应的人类疾病特征。基于我们对小鼠中该通路的了解，我们还能够测试以各种方式阻断该通路是否可以预防疾病。这项工作迈出了重要的一步，将多年来在模型系统中轴突变性方面的进展转化为对该途径如何在人类疾病中发生故障的真实的理解，从而走向可以预防或治疗疾病的疗法。

Axons are the long 'wires' that link one nerve cell to another. They are one of the first structures to be lost in almost all degenerative disorders of our brains, spinal cords and nerves. The consequences include pain, disability, loss of memory, hearing and sight in disorders such as Alzheimer's disease, motor neuron disease and multiple sclerosis. Peripheral neuropathies, disorders affecting the network of nerves outside the central nervous system, often resulting from diabetes or the side effects of cancer chemotherapy, are one example of an axonal disorder. Glaucoma, resulting from disruption of the optic nerve by pressure in the eye, is another.There are two main ways to study axon degeneration. One is in animal or cell culture models. These model systems bring major advantages for research, for example the underlying molecular mechanism can be studied in ways that would not be possible in humans, and drugs can be tested without risk to people. However, these models often do not fully represent the corresponding human disease. They are valid because we share much of our DNA sequence and most types of cells with other mammals, but there are always some limitations. The second, highly complementary approach is human genetics. Methods for sequencing and analysing human DNA have improved dramatically since the human genome was first sequenced and this is revolutionising our understanding of which genes may cause or contribute to common and rare disorders. However, ultimately these results are correlation rather than proof. Experimental model systems, such as those described above, are needed to extend this research. By studying axon degeneration in mouse, cell culture and fly models, we have made substantial progress in understanding an important axon degeneration mechanism. Animal models of disease have helped us understand its potential role in human disease and in normal ageing, the single biggest risk factor for many neurodegenerative disorders. Developments in human genetics have independently suggested that the proteins regulating axon degeneration in these model systems play a role in human disease, and generated far more data on how these proteins differ within the human population. The essential next steps are to understand how variations in these proteins within the human population can affect normal protein function, so we will make similar changes in animals or cell culture models to test whether features of the corresponding human diseases emerge. Based on our knowledge of the pathway in mice we are also able to test whether blocking this pathway in various ways can prevent disease. This work takes important steps towards translating years of progress in axon degeneration in model systems into real understanding of how the pathway malfunctions in human disease and hence towards therapies that can prevent or treat disease.