title: Parkinson Disease-linked Vps35 R524W Mutation Impairs the Endosomal Association of Retromer and Induces α-Synuclein Aggregation.
abstract: Endosomal sorting is a highly orchestrated cellular process. Retromer is a heterotrimeric complex that associates with endosomal membranes and facilitates the retrograde sorting of multiple receptors, including the cation-independent mannose 6-phosphate receptor for lysosomal enzymes. The cycling of retromer on and off the endosomal membrane is regulated by a network of retromer-interacting proteins. Here, we find that Parkinson disease-associated Vps35 variant, R524W, but not P316S, is a loss-of-function mutation as marked by a reduced association with this regulatory network and dysregulation of endosomal receptor sorting. Expression of Vps35 R524W-containing retromer results in the accumulation of intracellular α-synuclein-positive aggregates, a hallmark of Parkinson disease. Overall, the Vps35 R524W-containing retromer has a decreased endosomal association, which can be partially rescued by R55, a small molecule previously shown to stabilize the retromer complex, supporting the potential for future targeting of the retromer complex in the treatment of Parkinson disease.
authors.affiliation: From the Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland 4072, Australia and.
authors.forename: Jordan
authors.initials: J
authors.lastname: Follett
authors.affiliation: From the Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland 4072, Australia and.
authors.forename: Andrea
authors.initials: A
authors.lastname: Bugarcic
authors.affiliation: From the Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland 4072, Australia and.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Yang
authors.affiliation: From the Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland 4072, Australia and.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Ariotti
authors.affiliation: From the Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland 4072, Australia and.
authors.forename: Suzanne J
authors.initials: SJ
authors.lastname: Norwood
authors.affiliation: From the Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland 4072, Australia and.
authors.forename: Brett M
authors.initials: BM
authors.lastname: Collins
authors.affiliation: From the Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland 4072, Australia and the Centre for Microscopy and Microanalysis, University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Parton
authors.affiliation: From the Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland 4072, Australia and r.teasdale@uq.edu.au.
authors.forename: Rohan D
authors.initials: RD
authors.lastname: Teasdale
mesh_terms: D019943:Amino Acid Substitution; D011992:Endosomes; D006367:HeLa Cells; D006801:Humans; D020125:Mutation, Missense; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D066263:Protein Aggregation, Pathological / Q000235:genetics / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism
chemical_list: C497604:SNCA protein, human; C419573:VPS35 protein, human; D033921:Vesicular Transport Proteins; D051844:alpha-Synuclein
keywords: Parkinson disease; endosome; intracellular trafficking; membrane transport; protein sorting; retromer