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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.

Pubmed ID: 22899650


  • Berwick DC
  • Harvey K


Human molecular genetics

Publication Data

November 15, 2012

Associated Grants

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

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