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).

Abstract

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.

• Authors: Radek Linhart, Sarah Anne Wong, Jieyun Cao, Melody Tran, Anne Huynh, Casey Ardrey, Jong Min Park, Christine Hsu, Saher Taha, Rentia Peterson, Shannon Shea, Jason Kurian, Katerina Venderova
• Journal: Molecular neurodegeneration (Mol Neurodegener) Vol. 9 Pg. 23 (Jun 11 2014) ISSN: 1750-1326 [Electronic] England
• PMID: 24915984 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Drosophila Proteins
• Vesicular Transport Proteins
• Vps35 protein, Drosophila
• LRRK2 protein, Drosophila
• Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
• Protein Serine-Threonine Kinases

Topics

• Animals
• Animals, Genetically Modified
• Disease Models, Animal
• Drosophila Proteins (genetics, metabolism)
• Drosophila melanogaster (genetics, metabolism)
• Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
• Parkinson Disease (genetics, metabolism)
• Protein Serine-Threonine Kinases (genetics)
• Vesicular Transport Proteins (genetics, metabolism)