Mutation in VPS35 associated with Parkinson’s disease impairs WASH complex association and inhibits autophagy

Eszter Zavodszky,Matthew N.J Seaman,Sophia Y Breusegem,David C Rubinsztein,Maria Jimenez-Sanchez,Michael E Harbour,Kevin Moreau

doi:10.1038/ncomms4828

Eszter Zavodszky, Matthew N.J Seaman + Show 5 more

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https://doi.org/10.1038/ncomms4828

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Abstract

Endosomal protein sorting controls the localization of many physiologically important proteins and is linked to several neurodegenerative diseases. VPS35 is a component of the retromer complex, which mediates endosome-to-Golgi retrieval of membrane proteins such as the cation-independent mannose 6-phosphate receptor. Furthermore, retromer is also required for the endosomal recruitment of the actin nucleation promoting WASH complex. The VPS35 D620N mutation causes a rare form of autosomal-dominant Parkinson’s disease (PD). Here we show that this mutant associates poorly with the WASH complex and impairs WASH recruitment to endosomes. Autophagy is impaired in cells expressing PD-mutant VPS35 or lacking WASH. The autophagy defects can be explained, at least in part, by abnormal trafficking of the autophagy protein ATG9A. Thus, the PD-causing D620N mutation in VPS35 restricts WASH complex recruitment to endosomes, and reveals a novel role for the WASH complex in autophagosome formation.

Highlights

Endosomal protein sorting controls the localization of many physiologically important proteins and is linked to several neurodegenerative diseases
Our results indicate that the VPS35 D620N mutation and WASH1 depletion both impair ATG9A trafficking to autophagosomes
The retromer complex recruits the WASH complex to endosomes through VPS35 binding to the FAM21 protein[4,11,12,13]

Summary

Introduction

Endosomal protein sorting controls the localization of many physiologically important proteins and is linked to several neurodegenerative diseases. VPS35 is a component of the retromer complex, which mediates endosome-to-Golgi retrieval of membrane proteins such as the cation-independent mannose 6-phosphate receptor. The PD-causing D620N mutation in VPS35 restricts WASH complex recruitment to endosomes, and reveals a novel role for the WASH complex in autophagosome formation. The retromer complex is a conserved membrane-associated protein complex that functions in the endosome-to-Golgi retrieval pathway. The recruitment of the WASH complex to endosomes is mediated by interactions between the extended tail of the FAM21 protein of the WASH complex and VPS35 in the retromer CSC11–13. Autophagy is of profound importance in the clearance of intracytoplasmic aggregate-prone proteins, such as those formed by the polyglutamine-expanded repeats in huntingtin, the Huntington’s disease-causing protein, as well as a-synuclein, the major component of PD-associated Lewy bodies[23,24,25]. Depletion of yeast retromer components impairs autophagic activity, results in mammalian cells are at present unclear[28]

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