Fig. 5
Effect of LRRK2 kinase inhibition on canonical Wnt signalling. a HEK293 cells transfected with TOPflash and FLAG-DVL1 were treated with DMSO or LRRK2-in-1, TAE684, or CZC-25146 for 20 h at the indicated concentrations. Resultant luciferase values are expressed relative to DMSO controls. b-d The effect of kinase inhibion with these compounds was further analysed by comparing effects in wild-type and Lrrk2 knockout (KO) cells. b At concentrations used LRRK2 phosphorylation at serine-935 is reduced. c Using conditions identical to panel A, the three compounds also display differing effects in wild-type and Lrrk2 knockout cells. d The values produced for each inhibitor in panel C were expressed as a ratio of wild-type cells over knockout cells, indicating that LRRK2 inhibition weakens DVL1-driven canonical Wnt signalling. 1-way ANOVA reveals a significant effect of treatment (n = 12, F = 8.628, p < 0.001), with 2-sided Dunnett’s post-hoc analysis indicating significant differences between all treatments relative to control (LRRK2-in-1, p < 0.05; TAE684, p < 0.05; 1 μM CZC-25146, p < 0.01; 5 μM CZC-25146, p < 0.001)