title: The Vps35 D620N mutation linked to Parkinson's disease disrupts the cargo sorting function of retromer.
abstract: The retromer is a trimeric cargo-recognition protein complex composed of Vps26, Vps29 and Vps35 associated with protein trafficking within endosomes. Recently, a pathogenic point mutation within the Vps35 subunit (D620N) was linked to the manifestation of Parkinson's disease (PD). Here, we investigated details underlying the molecular mechanism by which the D620N mutation in Vps35 modulates retromer function, including examination of retromer's subcellular localization and its capacity to sort cargo. We show that expression of the PD-linked Vps35 D620N mutant redistributes retromer-positive endosomes to a perinuclear subcellular localization and that these endosomes are enlarged in both model cell lines and fibroblasts isolated from a PD patient. Vps35 D620N is correctly folded and binds Vps29 and Vps26A with the same affinity as wild-type Vps35. While PD-linked point mutant Vps35 D620N interacts with the cation-independent mannose-6-phosphate receptor (CI-M6PR), a known retromer cargo, we find that its expression disrupts the trafficking of cathepsin D, a CI-M6PR ligand and protease responsible for degradation of α-synuclein, a causative agent of PD. In summary, we find that the expression of Vps35 D620N leads to endosomal alterations and trafficking defects that may partly explain its action in PD.
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland,, Australia.
authors.forename: Jordan
authors.initials: J
authors.lastname: Follett
authors.forename: Suzanne J
authors.initials: SJ
authors.lastname: Norwood
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Hamilton
authors.forename: Megha
authors.initials: M
authors.lastname: Mohan
authors.forename: Oleksiy
authors.initials: O
authors.lastname: Kovtun
authors.forename: Stephanie
authors.initials: S
authors.lastname: Tay
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhe
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Wood
authors.forename: George D
authors.initials: GD
authors.lastname: Mellick
authors.forename: Peter A
authors.initials: PA
authors.lastname: Silburn
authors.forename: Brett M
authors.initials: BM
authors.lastname: Collins
authors.forename: Andrea
authors.initials: A
authors.lastname: Bugarcic
authors.forename: Rohan D
authors.initials: RD
authors.lastname: Teasdale
mesh_terms: D000368:Aged; D002402:Cathepsin D / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D011992:Endosomes / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D017527:Receptor, IGF Type 2 / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D017527:Receptor, IGF Type 2; C498296:VPS26A protein, human; C419572:VPS29 protein, human; C419573:VPS35 protein, human; D033921:Vesicular Transport Proteins; D002402:Cathepsin D
keywords: Parkinson's disease; Retromer; Vps35 D620N; cathepsin D; endosome