@article{discovery1367122, note = {{\copyright} The Author 2012. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. PMCID: PMC3709196}, month = {November}, pages = {4966 --4979}, journal = {Human Molecular Genetics}, volume = {21}, year = {2012}, title = {LRRK2 functions as a Wnt signaling scaffold, bridging cytosolic proteins and membrane-localized LRP6}, number = {22}, author = {Berwick, DC and Harvey, K}, url = {http://dx.doi.org/10.1093/hmg/dds342}, 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 {\ensuremath{\beta}}-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.}, issn = {1460-2083}, keywords = {Adaptor proteins, Signal transducing, Axin signaling complex, Cell line, Cell membrane, Cytosol, Humans, Ligands, Low density lipoprotein receptor-relatedprotein-6, Models, Biological, Mutation, Phosphoproteins, Protein binding, Protein transport, Protein-serine-threonine kinases, Wnt Proteins, Wnt signaling pathway} }