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The sheer length of motor neuron axons, that can carry electrical signals for up to a meter in humans, makes them susceptible to damage. Dr Cahir O'Kane uses fruitflies, and human disease genes, to study how axons are maintained, and how they go wrong in disease.
Motor neurons are among the longest cells known in animals. The 'cable' that transmits electrical signals, the axon, can be as much as a meter long in humans — tens of thousandfold longer than the central part (cell body) of the neuron, and requiring significant engineering to maintain it in good working condition.
What kinds of 'engineering' are required to keep axons working over such distances, and how can this go wrong during disease? The hereditary spastic paraplegias are a group of motor neuron diseases, with a wide spectrum of severity and age of onset, in which patients gradually lose the use of their lower limbs. This is due to progressive degeneration of motor axons in the spinal cord, with the most distal parts of the longer motor axons being worst affected. The spastic paraplegias have many genetic causes. Studying the engineering that maintains long motor axons can therefore help us to understand the disease mechanisms, allowing rational attempts at therapies; conversely, studying the disease causes can help us understand more of the fascinating biological processes that go on in axons.
To study these problems, we use the fruitfly Drosophila, which has a well developed nervous system. While it is much shorter lived than humans and has much shorter axons, its axons face challenges that are similar to those of human axons, although different in scale, and flies have most of the spastic paraplegia genes that humans also have. Much of our strategy involves generating flies that lack these genes, and understanding what then goes wrong — in order to predict what may be going wrong in the human diseases.
We have focused on the role of one intracellular organelle — the endoplasmic reticulum (ER), a continuous network of membranous tubules that extends all the way along the inside of axons, and is continuous with the ER in the rest of the neuron. Because of its continuity, it has been compared to a 'neuron within a neuron' — a structure that could allow regional or long-distance communication along the length of an axon, independent of the electrical signals at the cell surface. Many causative mutations for spastic paraplegia affect proteins that model this network, suggesting a role for it in axon maintenance.
We have explored this model by testing for abnormalities of the axonal ER network in mutant flies that lack specific spastic paraplegia genes. In some cases we see partial loss of ER from the parts of the axon furthest from the cell body, analogous to the defects seen in the human diseases. Other defects that we sometimes see include occasional loss of ER network continuity in axons – suggesting a model in which longer axons might be more susceptible to the disease because they are more likely to have a gap in the network.
Our work supports a role for spastic paraplegia genes in establishing or maintaining the axonal ER network, and a role for ER continuity that could account for the preferential susceptibility of longer axons to HSP. Our work now allows us to explore the physiological consequences for axons of defects in their ER network, and therefore of the pathogenic mechanisms by which degeneration might result.
Dr Cahir O'Kane is a group leader for the Drosophila Neural Cell Biology research group in the Department of Genetics