In HEK 293 cells stably expressing GFP-LRRK2[G2019S], LRRK2-IN-1 alters the cytoplasmic localization of LRRK2. In human-derived neuroblastoma SHSY5Y cells and mouse Swiss 3T3 cells, LRRK2-IN-1 induces a similar dose-dependent Ser910 and Ser935 dephosphorylation and loss of 14-3-3 binding to endogenous LRRK2. In transgenic C. elegans expressing human R1441C- and G2019S-LRRK2, LRRK2-IN1 rescues the behavioral deficit characteristic of dopaminergic impairment. In mouse fibroblasts, LRRK2-IN1 reduces cell motility. In AsPC-1 and HCT116 cell lines, LRRK2-IN-1 shows anti-proliferative and pro-apoptotic properties, induces G1 and G2/M cell cycle arrest and inhibits DCLK1 mRNA and protein expression.
In vivo
In wild type male C57BL/6 mice, LRRK2-IN-1 (100 mg/kg, i.p.) inhibits Ser910 and Ser935 dephosphorylation of LRRK2 in the kidney, while no effects in the brain.
