Fig. 1

Dose response of acute MLi-2 across brain and peripheral tissues. G2019S LRRK2 knock-in mice were given a single MLi-2 dose via oral gavage and sacrificed 1 h later. Brain, kidney, and lung homogenates were analyzed by western blot (N = 4 per group; 60 μg of protein were loaded per well). a, b, c Maximal LRRK2 inhibition was achieved at 10 mg/kg MLi-2 and plateaued with increasing MLi-2 amounts as seen in S1292 and S935 phosphorylation readouts across all tissues. d pT73 Rab10 showed variability in brain but significant dephosphorylation in peripheral tissues with treatment. e pS106 Rab12 showed a robust dose-dependent dephosphorylation across all tissues. f pT71 Rab29 showed variability but a trend of decrease across all tissues with treatment that reached maximal inhibition at the 30-60 mg/kg points. All dose response curves of the phospho-sites are shown in b-f and represent percentage over vehicle controls of phospho-levels normalized to total protein levels. IC50 values of Rab GTPases are generally higher and more variable across tissues compared to LRRK2 phosphorylation (IC50s were not reported when 50% reduction was not reached within the dose-response tested)