Exploring the therapeutic potential of Rab GTPases in Parkinson's disease

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Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterized by loss of dopaminergic neurons and the accumulation of misfolded synuclein (aSyn). Aberrant aSyn aggregation and consequent perturbed vesicular trafficking likely contribute to neurodegeneration. Rab GTPases play critical roles in vesicular trafficking in the cell, and have been implicated in the pathogenesis of PD. We have found that both Rab11 and Rab8a can strongly suppress disease phenotypes in models of PD. However, systematic testing of the 60 Rab family members in PD models has not been performed, and therapeutic strategies targeting these proteins are lacking. We recently performed a siRNA screen targeting Rab GTPase genes in mammalian cells to identify genes which modulate aSyn aggregation. We identified 22 genes, a subset of which will be investigated in this project. The student will assess modulation of aSyn-dependent disease-related phenotypes by candidate Rabs using biochemical and microscopy approaches. Alterations in synaptic vesicular release and Rab localisation due to aSyn will be examined using fluorescence and ultrastructural imaging of synaptic vesicles in neurons. The effects of Rabs upon aSyn disease phenotypes in Drosophila will also be examined. This work will provide important insight into the mechanisms and therapeutic potential of Rab GTPases in PD.