Endolysosomal Pathway in the Pathogenesis of Parkinson\u27s Disease

Parkinson’s disease (PD) is the most common movement neurodegenerative disorder. Its treatments are purely symptomatic and thus unable to halt or impede the progression of neuronal death. This is largely due to an incomplete understanding of the 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, Leucinerich repeat kinase 2 (LRRK2), and employed this model in a genome-wide modifier screen. Several of the discovered LRRK2 genetic interactors play a role in vesicular trafficking. One of these is VPS35, which we have selected 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 in the loss of dopaminergic neurons. Strikingly however, overexpression of VPS35 markedly extended the lifespan of rotenonetreated 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. From our experiments we conclude that LRRK2 regulates the retromer pathway and that this pathway plays a role in PD pathogenesis