Variability in human axon survival

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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.