Grant: Doctoral Award - Frederick Banting and Charles Best Canada Graduate Scholarships

Understanding the maintenance of neuronal function and the aetiology of neurodegenerative (ND) disorders is of great importance to an aging general public. We provide novel, fundamental insight regarding the regulation of gene expression in mature neurons that highlight a largely overlooked vulnerability to ND pathology. In development, neurons grow to innervate their target cells, at which time they receive target-derived signals that induce the expression of genes that are involved in neuronal function. However, we do not know whether this target-derived signaling is required continually to maintain mature neuronal gene expression in the adult nervous system. Using genetic techniques to control gene expression in subsets of adult Drosophila neurons, we have developed a model which shows that persistent target-derived signaling is required to maintain the expression of the neuropeptide FMRFa. We found that acute blockade of either specific signals from the target, or signaling transport mechanisms, using the familial amyotrophic lateral sclerosis (ALS) linked gene p150/Glued, in a subset of adult neurons dramatically downregulates FMRFa transcription. Furthermore, we provide evidence that neurons are able to restore normal gene expression after alleviation from disruptive pathologies caused by mutant p150/Glued expression. Given the evidence for target-dependent induction of important functional genes in Drosophila and vertebrates, we anticipate that target-dependent gene maintenance is widespread in the mature nervous system. This has important implications in light of the many ND diseases disrupt neuronal connectivity and axonal trafficking. Using our system we can test the basic mechanisms of pathology of major ND disease related genes and show that neurons may be able to fully recover normal gene expression if therapeutics are able to successfully alleviate those pathologies.