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The role of LRRK2 in Wnt signalling
We showed that dishevelled (DVL) family proteins interact with LRRK2. Importantly, DVL proteins mediate wingless (wnt) signalling pathways, leading to multiple downstream effects including the activation of small GTPases that are structurally similar to the LRRK2 Roc domain. Wnt signalling cascades play an important role in axon guidance, neurite outgrowth/ branching, synapse formation, differentiation of dopaminergic cells in the ventral midbrain, release and recycling of dopaminergic vesicles at presynaptic sites and have also been linked to neurodegeneration. The LRRK2 Roc-COR domain and the DVL DEP domain were necessary and sufficient for the LRRK2-DVL interaction. Co-expression of DVL increased LRRK2 steady-state protein levels, an effect that was dependent on the DEP domain. Strikingly, LRRK2-DVL interactions were modulated by familial PARK8 mutations. Co-expression of DVL with LRRK2 in mammalian cells resulted in redistribution of LRRK2 to typical cytoplasmic DVL aggregates in HEK293 and SH-SY5Y cells, and co-localisation in neurites and growth cones of differentiated dopaminergic SH-SY5Y cells (for details please refer to: Sancho et al 2009, Hum Mol Genet 15: 3955-3568). We have now shown the functional relevance of this interaction through investigating the effect of LRRK2 on Wnt signalling cascade activation in SH-SY5Y and HEK293 cells. Using a TCF-dependent reporter to measure activation of β-catenin-mediated transcription we revealed that LRRK2 was able to increase Wnt signalling activity. This effect could be abrogated by deleting the DVL DEP domain, which is important for DVL membrane targeting and the interaction with LRRK2. Both LRRK2 GTP binding and kinase activity were important for the effect on Wnt activity. In addition, LRRK2 interacts with key Wnt signalling proteins of the β-catenin destruction complex and is recruited to membranes following Wnt stimulation, where it binds to the Wnt co-receptor Lrp6. Changes in LRRK2 expression affect pathway activity, while all examined pathogenic LRRK2 mutants reduce both signal strength and the LRRK2-Lrp6 interaction. In conclusion, we have demonstrated that LRRK2 participates in canonical Wnt signalling as a scaffolding protein (Berwick and Harvey 2012, Hum Mol Genet 21: 4966-4979). Significantly, we have also acquired evidence that LRRK2 interacts with components of non-canonical Wnt signalling pathways. Therefore LRRK2 could contribute to multiple Wnt signalling pathways, explaining why LRRK2 has been found to influence so many different cell biological functions. It is also important to note that defining a role for LRRK2 in Wnt signalling has revealed multiple new targets for therapeutic interventions. A detailed investigation of the signalling changes caused by pathogenic LRRK2 mutations in specific branches of different Wnt signalling cascades will provide data underpinning the identification of therapeutic targets for a Parkinson’s disease-modifying treatment.
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