In vivo evidence of pathogenicity of VPS35 mutations in the Drosophila

Hua-Shan Wang,Eng-King Tan,Joanne Toh,Patrick Ho,Yi Zhao,Murni Tio

doi:10.1186/s13041-014-0073-y

Hua-Shan Wang, Eng-King Tan + Show 4 more

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https://doi.org/10.1186/s13041-014-0073-y

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Abstract

Mutations of VPS35, a component of the retromer complex have been associated with late onset familial Parkinson’s disease. The D620N mutation in VPS35 appears to be most prevalent, however, P316S was found in two cases within the same family and a control, whereas L774M was identified in 6 cases and 1 control. In vivo evidence of their pathogenicity is lacking. Here we investigated the in vivo effects of P316S, D620N and L774M using Drosophila as a model. We generated transgenic human VPS35-expressing mutations and demonstrated that VPS35 D620N transgenic flies led to late-onset loss of TH-positive DA neurons, poor mobility, shortened lifespans and increased sensitivity to rotenone, a PD-linked environmental toxin, with some of these phenotypes observed for P316S but not in L774M transgenic flies. We conclude that D620N and to a smaller extent P316S are associated with pathogenicity in PD.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-014-0073-y) contains supplementary material, which is available to authorized users.

Highlights

Parkinson’s disease (PD) is a neurodegenerative disorder that affects 1% of the aging population
There was no apparent difference at 20 days after eclosion across all genotypes (Figure 1A) but in aged 60 days old flies, we saw a significant loss of TH-positive DA neurons in the PPL1 clusters of VPS35 D620N mutant flies (p < 0.05) compared to age matched wild type and control flies (Figure 1B, C)
VPS35 is a component of the retromer complex recently linked to autosomal dominant late onset PD and in vivo evidence of pathogenicity of VPS35 mutations in single patient is lacking

Summary

Introduction

Parkinson’s disease (PD) is a neurodegenerative disorder that affects 1% of the aging population. It is characterized by the loss of midbrain dopaminergic (DA) neurons in the substantia nigra region as well as accumulation of Lewy body aggregates. VPS35 encodes for a subunit of the retromer, a coat-like protein complex that is involved in the recycling of membrane proteins. A number of reports determined a link between mutations in VPS35 and familial late-onset PD [4,5]. Successive studies showed that D620N mutation in VPS35 is the most prevalent and found to be associated with autosomal dominant PD in Caucasian and Japanese

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