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

Human molecular genetics | Nov 15, 2012

http://www.ncbi.nlm.nih.gov/pubmed/22899650

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.

Pubmed ID: 22899650 RIS Download

Mesh terms: Adaptor Proteins, Signal Transducing | Axin Signaling Complex | Cell Line | Cell Membrane | Cytosol | Humans | Ligands | Low Density Lipoprotein Receptor-Related Protein-6 | Models, Biological | Mutation | Phosphoproteins | Protein Binding | Protein Transport | Protein-Serine-Threonine Kinases | Wnt Proteins | Wnt Signaling Pathway

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Associated grants

  • Agency: Wellcome Trust, Id: WT088145AIA
  • Agency: Wellcome Trust, Id: WT095010MA

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