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

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

doi:10.1038/ncomms4828

journal article Open Access May 13, 2014

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

Eszter Zavodszky Matthew N.J. Seaman Kevin Moreau Maria Jimenez-Sanchez

Sophia Y. Breusegem Michael E. Harbour

David C. Rubinsztein

Nature Communications Vol. 5 No. 1 · Springer Science and Business Media LLC

View at Publisher Save 10.1038/ncomms4828

Abstract

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.

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Published: May 13, 2014
Vol/Issue: 5(1)
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Authors

Maria Jimenez-Sanchez

Cite This Article

Eszter Zavodszky, Matthew N.J. Seaman, Kevin Moreau, et al. (2014). Mutation in VPS35 associated with Parkinson’s disease impairs WASH complex association and inhibits autophagy. Nature Communications, 5(1). https://doi.org/10.1038/ncomms4828

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

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