Analysis of the Retromer complex-WASH complex interaction illuminates new avenues to explore in Parkinson disease

Abstract

The retromer complex mediates endosomal protein sorting by concentrating membrane proteins (cargo) into nascent tubules formed through the action of sorting nexin (SNX) proteins. The WASH complex is recruited to endosomes by binding to the VPS35 subunit of retromer and facilitates cargo protein sorting by promoting formation of endosomally-localized F-actin. The VPS35 protein is mutated in Parkinson disease (PD) and a recent report has revealed that the PD-causing mutation impairs the association of retromer with the WASH complex leading to perturbed endosomal protein sorting. Another important player in endosomal protein sorting is the DNAJC13/RME-8 protein, which associates with SNX1 and has also recently been linked to PD. An additional recent report has now shown that RME-8 also interacts with the WASH complex thus establishing retromer and WASH complex-mediated endosomal protein sorting as a key pathway linked to the pathology of PD and providing new avenues to explore in the search for insights into the disease mechanism.