Genetic Analysis of Neurodegeneration

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Neurodegenerative diseases are common and devastating disorders, which will become increasingly prevalent as our population ages. Unfortunately, despite years of effort and some promising leads, we still do not have disease-modifying therapies. To provide an alternative approach to studying these disorders and identifying potential therapeutics we have pioneered the use of Drosophila as a model system for studying neurodegeneration, with a particular emphasis on Parkinson’s disease and Alzheimer’s disease. Our studies have allowed us to identify genes controlling neurodegeneration in our fly models. We have subsequently verified these findings in vertebrate models of the diseases, in postmortem brain tissue from patients and in patient-derived cells. In the current proposal we will capitalize on our prior progress by exploring in mechanistic detail the role alterations of the spectrin cytoskeleton play in promoting neurodegeneration in α-synucleinopathies. Specifically, we will test the hypothesis that α-synuclein binds to the ankyrin-binding domain of ß-spectrin and thereby perturbs autophagosome transport and maturation. We have recently developed a powerful new model of α-synuclein toxicity in Drosophila. Our previous model showed striking specificity for dopaminergic neurons. While valuable for exploring toxicity to dopamine neurons, a very important cell type for Parkinson’s disease, the restricted pathology present limited implementation of large-scale genetic screens. We have therefore created a model of α-synuclein neurotoxicity in which age-dependent neurodegeneration is significantly more widespread. Our new model has facilitated completion of a genome-scale genetic screen, an important strength of Drosophila models. Importantly, our new α-synucleinopathy model employs a dual transcriptional system we have developed, which allows simultaneous and independent manipulation of gene expression, at scale, in neurons and glia. We can now define the broad complement of mechanisms by which glia control toxicity of α-synuclein in neurons non-cell autonomously. Given the growing evidence for an important role for glia in neurodegenerative disease, these studies have the potential for significant impact.