Investigating the mechanisms of axonal degeneration in amyotrophic lateral sclerosis using Drosophila and mouse transgenics

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ALS is a devastating, progressive, paralysing disease, which kills over 1200 people in the UK each year, usually within 3-5 years of onset. It usually affects people in their 50s and older, but it can affect adults of any age. Despite decades of research, ALS remains incurable and medical care is essentially palliative (ventilator machines and feeding tubes). The causes of ALS are not fully understood, but in about 10% of cases there may be a family history of ALS suggesting a genetic cause. Excitingly, the past five years has seen an explosion in our understanding of ALS with the discovery of many genes linked to ALS. One of the most important genes is TDP-43. Recent breakthrough research has found that 95% of patients with ALS have clumps of TDP-43 in their brains and spinal cords. In some patients the gene that produces TDP-43 is also mutated and we now believe that TDP-43 plays an important role in causing almost all cases of ALS. Thus, researchers believe that TDP-43 models of ALS will be critical to working out the fundamental causes of ALS, and, ultimately, to develop desperately needed treatments for ALS. Another important consideration for scientists is understanding how ALS begins, because tackling ALS in the early stages is likely to be the most effective way of treating it. ALS is characterised by the loss of nerve cells called motoneurones. These cells have long, delicate processes, called axons, which connect them to other nerve cells and also muscles, allowing us to move, swallow and breathe. In ALS the very earliest signs of disease appear in these axons. We therefore believe that by protecting these axons we can prevent the very earliest stages of ALS. Excitingly, two protective factors have been discovered, which dramatically protect axons when they are cut. However, these factors have never been tested in TDP-43 models of ALS. I plan to test these factors in genetically modified TDP-43 fruitflies and mice, which mimic ALS. I also plan to use these models to find new ways of protecting axons in ALS, which could open up whole new avenues of research. I shall be conducting this research in the labs of Dr Coleman and Dr Freeman, the two world-leading axon experts who discovered these protective factors.Flies are an excellent model for scientists as they have very similar genes to humans, including TDP-43, and have similar types of motoneurons, muscles and brains. We will use novel cutting edge techniques to rapidly test the potential of axon protective factors. We still have to confirm our fly discoveries in mice (as mammals, mice are more similar to humans than flies and of course we ultimately want to develop treatments for patients). However, by starting our experiments in flies, we will limit the numbers of mice we use to an absolute minimum. We will also use nerve cells from patients with ALS, which have been created from skin biopsies using revolutionary stem cell technology. One of the most exciting aspects of our planned research is that it aims to not only push forward our understanding of the mechanisms underlying ALS, it also aims to simultaneously identify ways of protecting axons in animal models. This research therefore holds great promise for finding therapeutic targets that can ultimately benefit patients with ALS. Furthermore, our work may well benefit patients with a whole range of other brain diseases, which also display axon degeneration with or without TDP-43 clumps, including Alzheimer's disease and Parkinson's disease. The research we propose therefore has the potential to benefit many thousands of people with incurable and devastating degenerative diseases.