McCarron, K.R., Elcocks, H., Mortiboys, H. orcid.org/0000-0001-6439-0579 et al. (2 more authors) (2024) The Parkinson's disease related mutant VPS35 (D620N) amplifies the LRRK2 response to endolysosomal stress. Biochemical Journal, 481 (4). pp. 265-278. ISSN 0264-6021
Abstract
The identification of multiple genes linked to Parkinson's disease (PD) invites the question as to how they may co-operate. We have generated isogenic cell lines that inducibly express either wild-type or a mutant form of the retromer component VPS35 (D620N), which has been linked to PD. This has enabled us to test proposed effects of this mutation in a setting where the relative expression reflects the physiological occurrence. We confirm that this mutation compromises VPS35 association with the WASH complex, but find no defect in WASH recruitment to endosomes, nor in the distribution of lysosomal receptors, cation-independent mannose-6-phosphate receptor and Sortilin. We show VPS35 (D620N) enhances the activity of the Parkinson’s associated kinase LRRK2 towards RAB12 under basal conditions. Furthermore, VPS35 (D620N) amplifies the LRRK2 response to endolysosomal stress resulting in enhanced phosphorylation of RABs 10 and 12. By comparing different types of endolysosomal stresses such as the ionophore nigericin and the membranolytic agent l-leucyl-l-leucine methyl ester, we are able to dissociate phospho-RAB accumulation from membrane rupture.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2024 The Author(s). This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (https://creativecommons.org/licenses/by/4.0/). |
Keywords: | LRRK2; Parkinson's disease; VPS35; lysosomes; retromer; Humans; Parkinson Disease; Vesicular Transport Proteins; Mutation; Lysosomes; Endosomes; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine and Population Health |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 08 Mar 2024 17:08 |
Last Modified: | 08 Mar 2024 17:08 |
Status: | Published |
Publisher: | Portland Press Ltd. |
Refereed: | Yes |
Identification Number: | 10.1042/bcj20230492 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:209872 |