Parkinson disease-linked Vps35 R524W mutation impairs the endosomal association of retromer and induces α-synuclein aggregation

Follett, Jordan, Bugarcic, Andrea, Yang, Zhe, Ariotti, Nicholas, Norwood, Suzanne J., Collins, Brett M., Parton, Robert G. and Teasdale, Rohan D. (2016) Parkinson disease-linked Vps35 R524W mutation impairs the endosomal association of retromer and induces α-synuclein aggregation. Journal of Biological Chemistry, 291 35: 18283-18298. doi:10.1074/jbc.M115.703157

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Author Follett, Jordan
Bugarcic, Andrea
Yang, Zhe
Ariotti, Nicholas
Norwood, Suzanne J.
Collins, Brett M.
Parton, Robert G.
Teasdale, Rohan D.
Title Parkinson disease-linked Vps35 R524W mutation impairs the endosomal association of retromer and induces α-synuclein aggregation
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
1083-351X
Publication date 2016-08-26
Sub-type Article (original research)
DOI 10.1074/jbc.M115.703157
Open Access Status File (Publisher version)
Volume 291
Issue 35
Start page 18283
End page 18298
Total pages 16
Place of publication Bethesda, MD, United States
Publisher American Society for Biochemistry and Molecular Biology
Language eng
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.
Keyword Endosome
Intracellular trafficking
Membrane transport
Parkinson disease
Protein sorting
Retromer
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
Centre for Microscopy and Microanalysis Publications
 
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Created: Sat, 01 Oct 2016, 00:07:34 EST by Susan Allen on behalf of Institute for Molecular Bioscience