Parkinson's disease is the most common neurodegenerative movement disorder and is characterized pathologically by the intraneuronal deposition of abnormally phosphorylated and aggregated ?-synuclein protein. Abnormal deposition of ?-synuclein into neuronal and glial aggregates is also the primary pathologic feature of a group of collectively even more common disorders, termed the ?-synucleinopathies. To define the molecular mechanisms controlling ?-synuclein induced neurodegeneration we and others have modeled ?-synucleinopathies in the simple and powerful genetic model organism Drosophila. Genetic, biochemical and cell biological experiments in Drosophila have provided important clues regarding the pathogenesis of ?-synucleinopathies. However, the unbiased forward genetic screens providing the bases for these studies, while valuable, have to date remained incomplete. Here we propose to use a newly created and powerful Drosophila model of ?-synucleinopathies to perform a comprehensive genetic analysis of ?-synuclein neurotoxicity in vivo. These studies will for the first time provide a broad analysis of mechanisms controlling ?-synuclein toxicity to postmitotic neurons and should identify many new high-value therapeutic targets. Our studies will be particularly important as more and more data emerges from genome wide associated studies showing genetic influences on Parkinson's disease and related ?-synucleinopathies, but with little clear evidence as to the mechanism of action of these newly identified gene products in neurodegenerative disease pathogenesis.
The proposed studies will combine the strengths of fruit flies as a fast, cheap model system to identify causal factors in neurodegeneration caused by toxicity of the synaptic protein ?-synuclein. These studies will help us identify therapeutic targets in Parkinson's disease and related neurodegenerative disorders.
| Ordonez, Dalila G; Lee, Michael K; Feany, Mel B (2018) ?-synuclein Induces Mitochondrial Dysfunction through Spectrin and the Actin Cytoskeleton. Neuron 97:108-124.e6 |
