Elucidating early stage ALS pathomecanisms that drive mitochondrial dysfunction

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Motor neurons are the nerves that send signals from the spinal cord to our muscles. They are amongst the largest nerve cells in the body and are highly specialized, in that their cell body is located in the spinal cord and its fibre (called the 'axon') projects outside to the muscles; these cells have huge energy demands because they are so big and active.Amyotrophic Lateral Sclerosis (ALS) is a relentless and incurable disease that kills the motor neurons, resulting in progressive paralysis and death typically within 5 years of diagnosis. ALS has a lifetime risk of 1 in 250 in the UK population, and although it is mainly considered a disorder of mid-life, children as young as 11 years of age have been diagnosed with ALS. We have a desperate need to find some kind of treatment for this disease - however, we do not yet know the fundamental reasons why motor neurons die in ALS, or even when the disease processes start, so we cannot tackle these processes with targeted therapies.Every cell in our body contains DNA, RNA and proteins. DNA is in the nucleus of cells and carries the information on how to build the proteins. Proteins are the building block of our cells and they can also perform important tasks for the normal functioning of cells. RNA is the intermediate and carries the instructions for making individual proteins from the DNA, to the various locations inside a cell where these proteins are made and needed for specific jobs.90% of ALS is 'sporadic' -- it occurs in people who have no family history of the disease. However, ~10% occurs in families and usually if a parent is affected there is a 50% chance a child will have ALS. There are many mutant genes that can cause ALS in these familial cases. Some of these genes give the instructions to make proteins that bind to RNA and enable RNA to work properly in the cell. While we know that several of these 'RNA binding proteins', can be mutated in ALS, and cause motor neurons to die, we do not know how this happens, or when it begins.Here, we have created a unique system, for starting to understand why motor neurons die in one form of familial ALS, caused by mutations in an RNA binding protein called 'FUS'. This system is based on a new antibody that just binds to the mutant FUS protein. We have a FUS mouse model - which has a human mutation recognised by the antibody - that causes progressive motor neuron loss in the animal. We will now make a complementary human cell line with the same mutation. Having this antibody means we can now look at how mutant FUS behaves differently from the normal FUS protein. We can start to see what aberrant processes the mutant protein is involved in, and where these happen in the motor neuron and other cells.This antibody system has already told us that changes in proteins and energy balance, and in fats, occur early, before we see motor neuron death in our mouse model. Thus, working with our system, and comparing our findings with our human FUS-ALS cells, will make an important contribution to our understanding of ALS, particularly in the early stages before motor neurons have died. This this research will help us to target therapies in this form of ALS, and, we believe, shed light on other forms of ALS that arise from aberrant RNA binding proteins.