The Vps35 D620N mutation linked to Parkinson's disease disrupts the cargo sorting function of retromer

Follett, Jordan, Norwood, Suzanne J., Hamilton, Nicholas A., Mohan, Megha, Kovtun, Oleksiy, Tay, Stephanie, Yang, Zhe, Wood, Stephen A., Mellick, George D., Silburn, Peter A., Collins, Brett M., Bugarcic, Andrea and Teasdale, Rohan D. (2014) The Vps35 D620N mutation linked to Parkinson's disease disrupts the cargo sorting function of retromer. Traffic, 15 2: 230-244. doi:10.1111/tra.12136

Author Follett, Jordan
Norwood, Suzanne J.
Hamilton, Nicholas A.
Mohan, Megha
Kovtun, Oleksiy
Tay, Stephanie
Yang, Zhe
Wood, Stephen A.
Mellick, George D.
Silburn, Peter A.
Collins, Brett M.
Bugarcic, Andrea
Teasdale, Rohan D.
Title The Vps35 D620N mutation linked to Parkinson's disease disrupts the cargo sorting function of retromer
Journal name Traffic   Check publisher's open access policy
ISSN 1398-9219
Publication date 2014-02-01
Year available 2013
Sub-type Article (original research)
DOI 10.1111/tra.12136
Open Access Status
Volume 15
Issue 2
Start page 230
End page 244
Total pages 15
Place of publication Malden, MA, United States
Publisher Wiley-Blackwell
Language eng
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.
Keyword Retromer
Vps35 D620N
Parkinson's disease
Cathepsin D
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID APP511072
Institutional Status UQ
Additional Notes Article first published online: 14 November 2013.

Document type: Journal Article
Sub-type: Article (original research)
Collections: UQ Centre for Clinical Research Publications
Official 2014 Collection
Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 68 times in Thomson Reuters Web of Science Article | Citations
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Created: Fri, 22 Nov 2013, 20:30:24 EST by Susan Allen on behalf of Institute for Molecular Bioscience