Vesicular trafficking in the pathogenesis of Parkinsons disease. Katerina Venderova¹, Sarah Wong¹, Jieyun Cao¹, Radek Linhart¹, Melody Tran¹, Casey Ardrey¹, Christine Hsu¹, Anne Huynh¹, Jong Min Park¹, Brian Phi¹, Gina Stassinos¹, Edwin Yadidi¹, Matthew Seaman². 1) University of the Pacific, Stockton, CA; 2) University of Cambridge, Cambridge, UK.

   Parkinsons disease (PD) is the most common movement neurodegenerative disorder. Its treatments are purely symptomatic and thus unable to halt or slow down the progression of the neuronal death. This is largely due to an incomplete understanding of molecular pathways involved in the disease process. To address this gap, we have previously generated a Drosophila model of PD that overexpresses the most common causative gene of PD, leucine-rich repeat kinase 2 (LRRK2), and employed this model in a genome-wide modifier screen. Several of the uncovered LRRK2 genetic interactors played a role in vesicular trafficking, and we have selected VPS35 for further studies. VPS35 is a core component of the retromer complex that is essential for sorting and recycling specific cargo proteins from endosomes to the trans-Golgi network. We observed that overexpression of VPS35 significantly ameliorated the mutant hLRRK2 eye phenotype. We next exposed the flies to rotenone - a neurotoxin commonly used in PD research. As we have shown previously, overexpression of mutant hLRRK2 makes flies more sensitive to rotenone, both in terms of lifespan and loss of dopaminergic neurons. Strikingly however, overexpression of VPS35 markedly extended the lifespan of mutant LRRK2-overexpressing flies. Furthermore, VPS35 overexpression significantly protected from the locomotor deficits observed in mutant LRRK2 flies, as assessed by the negative geotaxis assay. This protection was seen throughout the lifespan, and confirmed with two independent VPS35 lines. We are currently processing brains of these flies for staining and quantification of dopaminergic neurons. From our experiments we conclude that LRRK2 regulates the retromer pathway and that this pathway plays a role in PD pathogenesis.