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Background  Parkinson’s disease (PD) is the most common movement neurodegenerative movement disorder. An incomplete understanding of the molecular pathways involved in its pathogenesis impedes the development of effective disease-modifying treatments. To address this gap, we have previously generated a  Drosophila  model of PD that overexpresses PD pathogenic mutant form of the second most common causative gene of PD, Leucine-Rich Repeat Kinase 2  (LRRK2).Findings  We employed this model in a genetic modifier screen and identified a gene that encodes for a core subunit of retromer – a complex essential for the sorting and recycling of specific cargo proteins from endosomes to the trans-Golgi network and cell surface. We present evidence that overexpression of the Vps35 or Vps26 component of the cargo-recognition subunit of the retromer complex ameliorates the pathogenic mutant  LRRK2  eye phenotype. Furthermore, overexpression of  Vps35  or  Vps26  significantly protects from the locomotor deficits observed in mutant  LRRK2  flies, as assessed by the negative geotaxis assay, and rescues their shortened lifespan. Strikingly, overexpressing  Vps35  alone protects from toxicity of rotenone, a neurotoxin commonly used to model parkinsonism, both in terms of lifespan and locomotor activity of the flies, and this protection is sustained and even augmented in the presence of mutant  LRRK2 . Finally, we demonstrate that knocking down expression of  Vps35  in dopaminergic neurons causes a significant locomotor impairment.    Conclusions  From these results we conclude that LRRK2 plays a role in the retromer pathway and that this pathway is involved in PD pathogenesis.

molecular neurodegeneration

Vacuolar protein sorting 35 (Vps35) rescues locomotor deficits and shortened lifespan in Drosophila expressing a Parkinson’s disease mutant of Leucine-rich repeat kinase 2 (LRRK2)