LRRK2 functions as a Wnt signaling scaffold, bridging cytosolic proteins and membrane-localized LRP6.
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.
Department of Pharmacology, UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, UK.
Daniel C
DC
Berwick
Kirsten
K
Harvey
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D060465:Axin Signaling Complex / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism*; D000072261:Dishevelled Proteins; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008024:Ligands; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D010750:Phosphoproteins / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway
D048868:Adaptor Proteins, Signal Transducing; D060465:Axin Signaling Complex; D000072261:Dishevelled Proteins; D008024:Ligands; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D010750:Phosphoproteins; D051153:Wnt Proteins; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases