Molecular chaperone function and motor neuron degeneration

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In order to co-ordinate movement, signals must be sent from the brain to the muscles along specialized nerve cells called motor neurons. Some of these motor neurons are very large and send signals over several feet, this makes their biology very challenging and means that they can be susceptible to stress and disease. When these motor neurons die it leads to paralysis. In some families this paralysis can be inherited because of genetic changes. Recently, it was discovered that inherited changes in a stress response protein called HSJ1 lead to paralysis through the death of motor neurons. We have been studying this protein for many years and know that it can protect nerve cells, including motor neurons, from stress. To function normally all cells need to balance their production of new proteins with their removal and this is especially important at times of stress, when proteins can get damaged. Therefore, evolution has developed a family of proteins called molecular chaperones to help maintain this balance and HSJ1 is an important molecular chaperone in nerve cells. To investigate how HSJ1 functions in nerve cells and understand why it is so critical to motor neurons, we have now reprogrammed cells from patients with inherited paralysis and will use them to study human motor neurons. We also have developed an animal model that mimics the human disease. In this project we will use these models to discover the molecular basis for paralysis in patients. It is likely that the events that cause paralysis in this disease will also affect how motor neurons function in other diseases and therefore we think this will tell us more about other types of motor neuron disease and nerve cell death in general. We will also use this detailed molecular understanding to develop new treatments that might be used for this type of paralysis and potentially other forms of nerve cell death such as motor neuron disease, Parkinson's and Alzheimer's disease.