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  • The Vps35 D620N Mutation Linked to Parkinson's Disease Disrupts the Cargo Sorting Function of Retromer

    Author(s)
    Follett, Jordan
    Norwood, Suzanne J
    Hamilton, Nicholas A
    Mohan, Megha
    Kovtun, Oleksiy
    Tay, Stephanie
    Zhe, Yang
    Wood, Stephen A
    Mellick, George D
    Silburn, Peter A
    Collins, Brett M
    Bugarcic, Andrea
    Teasdale, Rohan D
    Griffith University Author(s)
    Mellick, George
    Year published
    2014
    Metadata
    Show full item record
    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 ...
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    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 a-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.
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    Journal Title
    Traffic
    Volume
    15
    Issue
    2
    DOI
    https://doi.org/10.1111/tra.12136
    Subject
    Biochemistry and cell biology
    Cellular interactions (incl. adhesion, matrix, cell wall)
    Medical microbiology
    Publication URI
    http://hdl.handle.net/10072/63879
    Collection
    • Journal articles

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