Grant: Operating Grant

ALS, also known as Lou Gehrig's disease, is a devastating neurodegenerative disorder caused by progressive loss of motor neuron function in the brain and spinal cord. Eventually patients will not be able to stand, walk, or use their hands and arms. Most people with ALS die of respiratory failure or pneumonia caused by weakness of the respiratory muscle within two to five years after onset. There is no primary therapy for ALS. It is therefore important to understand the mechanism by which this disease occurs, as this may allow us to develop a future therapy for ALS. One approach is the use of genetic analysis in Drosophila (commonly known as fruit flies) to identify the genetic pathways leading to pathology of ALS. The information gained from this work has also been applied to studies in mice and human. A large body of work has convincingly demonstrated the great degree to which genes and genetic pathways are conserved between Drosophila and mammals, and recent studies indicate that this conservation of molecular mechanisms also makes Drosophila an excellent system in which to model human diseases. For example, our preliminary studies have shown that flies expressing the mutant protein identified in a familial form of ALS (ALS8) recapitulate many of the characteristic features of the disease. Importantly, based on the data from Drosophila studies, we have discovered that a novel hormone derived from ALS8 protein (VAP MSP) is secreted into the blood and that the serum levels of VAP MSP in ALS8 patients are decreased. This hormone might contribute to the pathogenesis of ALS, just like decreasing insulin levels cause diabetes mellitus. Hence, studies in Drosophila and mice provide a productive approach to understand the molecular mechanisms underlying the pathogenesis of ALS. We believe that this project will enable us to advance our understanding of the mechanisms of ALS and provide insight towards developing more effective treatment.