Atypical parkinsonism-associated retromer mutant alters endosomal sorting of specific cargo proteins

Kirsty J McMillan, Matthew J Gallon, Adam P. Jellett, Thomas Clairfeuille, Frances C. Tilley, Ian McGough, Chris M. Danson, Kate J Heesom, Kevin A Wilkinson, Brett M. Collins, Peter J Cullen*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

33 Citations (Scopus)
618 Downloads (Pure)


The retromer complex acts as a scaffold for endosomal protein complexes that sort integral membrane proteins to various cellular destinations. The retromer complex is a heterotrimer of VPS29, VPS35, and VPS26. Two of these paralogues, VPS26A and VPS26B, are expressed in humans. Retromer dysfunction is associated with neurodegenerative disease, and recently, three VPS26A mutations (p.K93E, p.M112V, and p.K297X) were discovered to be associated with atypical parkinsonism. Here, we apply quantitative proteomics to provide a detailed description of the retromer interactome. By establishing a comparative proteomic methodology, we identify how this interactome is perturbed in atypical parkinsonism-associated VPS26A mutants. In particular, we describe a selective defect in the association of VPS26A (p.K297X) with the SNX27 cargo adaptor. By showing how a retromer mutant leads to altered endosomal sorting of specific PDZ ligand-containing cargo proteins, we reveal a new mechanism for perturbed endosomal cargo sorting in atypical parkinsonism.

Original languageEnglish
Pages (from-to)389-399
Number of pages11
JournalJournal of Cell Biology
Issue number4
Publication statusPublished - 15 Aug 2016


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