Dissecting alpha-synuclein pathology in Drosophila models of Parkinson's Disease: aids to understanding idiopathic Parkinson's Disease. (360G-Wellcome-090541_Z_09_Z)

My research project will use Drosophila melanogaster to model novel mutations in the GBA, PANK2 and PLA2G6 genes known to cause parkinsonism and ?-synuclein pathology in humans, in order to identify common pathogenic pathways in idiopathic PD. This will involve knockout of the GBA, PANK2 and PLA2G6 genes and also expression of PD-associated mutant forms of these genes in Drosophila neural tissue, both in the presence and absence of ?-synuclein expression. These fly models will be characterised, including the effect on longevity, locomotor ability and neuronal viability. I will then study the role of ceramide metabolism in these PD models by comparing the temporo-spatial relationships between these neurotoxic phenotypes and abnormalities in ceramide metabolism. Furthermore I will identify links between ceramide levels and downstream effectors such as mitochondrial, autophagy-lysosomal and proteasomal pathways. In addition, I will determine how loss of function of GBA, PANK2 and PLA2G6 gene products affect the onset and severity of ?-synuclein pathology in flies co-expressing ?- synuclein. In particular, I am interested to determine how these mutations differentially affect the soluble and insoluble pools of ?-synuclein in fly brains. Finally, I will use these fly models as a platform of drug discovery to screen compounds that are predicted to interfere and protect against neurodegeneration by altering ceramide and autophagy pathways.