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)

Molecular Neurodegeneration

Katerina Venderova¹  Jason Kurian¹  Shannon Shea¹  Rentia Peterson¹  Saher Taha¹  Christine Hsu¹  Jong Min Park¹  Casey Ardrey¹  Anne Huynh¹  Melody Tran¹  Jieyun Cao¹  Sarah Anne Wong¹  Radek Linhart¹ 

[1] Department of Physiology and Pharmacology, Thomas J. Long School of Pharmacy and Health Sciences, University of the Pacific, 751 Brookside Rd, Stockton, CA 95211, USA

关键词: VPS26;    Lysosome;    Endosomes;    Neurodegeneration;    Rotenone;    Genetics;    Drosophila;    Endolysosomal pathway;    Retromer;    VPS35;    LRRK2;    Parkinson’s disease;   

Others  :  1138837
DOI  :  10.1186/1750-1326-9-23

 received in 2013-09-09, accepted in 2014-05-09,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Linhart et al.; licensee BioMed Central Ltd.

【 图 表 】

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