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LRRK2 functions as a Wnt signaling scaffold, bridging cytosolic proteins and membrane-localized LRP6

Berwick, Daniel C. and Harvey, Kirsten (2012). LRRK2 functions as a Wnt signaling scaffold, bridging cytosolic proteins and membrane-localized LRP6. Human Molecular Genetics, 21(22) pp. 4966–4979.

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DOI (Digital Object Identifier) Link: https://doi.org/10.1093/hmg/dds342
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Abstract

Mutations in PARK8, encoding leucine-rich repeat kinase 2 (LRRK2), are a frequent cause of Parkinson's disease (PD). Nonetheless, the physiological role of LRRK2 remains unclear. Here, we demonstrate that LRRK2 participates in canonical Wnt signaling as a scaffold. LRRK2 interacts with key Wnt signaling proteins of the β-catenin destruction complex and dishevelled proteins in vivo and is recruited to membranes following Wnt stimulation, where it binds to the Wnt co-receptor low-density lipoprotein receptor-related protein 6 (LRP6) in cellular models. LRRK2, therefore, bridges membrane and cytosolic components of Wnt signaling. Changes in LRRK2 expression affects pathway activity, while pathogenic LRRK2 mutants reduce both signal strength and the LRRK2-LRP6 interaction. Thus, decreased LRRK2-mediated Wnt signaling caused by reduced binding to LRP6 may underlie the neurodegeneration observed in PD. Finally, a newly developed LRRK2 kinase inhibitor disrupted Wnt signaling to a similar extent as pathogenic LRRK2 mutations. The use of LRRK2 kinase inhibition to treat PD may therefore need reconsideration.

Item Type: Journal Item
Copyright Holders: 2012 The Authors
ISSN: 1460-2083
Academic Unit/School: Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences
Faculty of Science, Technology, Engineering and Mathematics (STEM)
Item ID: 44275
Depositing User: Daniel Berwick
Date Deposited: 06 Oct 2015 11:18
Last Modified: 23 May 2019 16:49
URI: http://oro.open.ac.uk/id/eprint/44275
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