Leucine-rich repeat kinase 2 functionally interacts with microtubules and kinase-dependently modulates cell migration

Recent studies indicate that the Parkinson's disease-linked leucine-rich repeat kinase 2 (LRRK2) modulates cytoskeletal functions by regulating actin and tubulin dynamics, thereby affecting neurite outgrowth. By interactome analysis we demonstrate that the binding of LRRK2 to tubulins is significantly enhanced by pharmacological LRRK2 inhibition in cells. Co-incubation of LRRK2 with microtubules increased the LRRK2 GTPase activity in a cell-free assay. Destabilization of microtubules causes a rapid decrease in cellular LRRK2(S935) phosphorylation indicating a decreased LRRK2 kinase activity. Moreover, both human LRRK2(G2019S) fibroblasts and mouse LRRK2(R1441G) fibroblasts exhibit alterations in cell migration in culture. Treatment of mouse fibroblasts with the selective LRRK2 inhibitor LRRK2-IN1 reduces cell motility. These findings suggest that LRRK2 and microtubules mutually interact both in non-neuronal cells and in neurons, which might contribute to our understanding of its pathogenic effects in Parkinson's disease.

► LRRK2 inhibition promotes LRRK2-tubulin protein interaction.
► Microtubule destabilization decreases LRRK2(S935) phosphorylation.
► Co-incubation with tubulins increases LRRK2 GTPase activity.
► Cell migration in enhanced in fibroblasts carrying LRRK2 mutations.
► LRRK2 inhibition slows fibroblast migration.