title: Leucine-rich repeat kinase 2 functionally interacts with microtubules and kinase-dependently modulates cell migration.
abstract: 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.
authors: Boehringer Ingelheim Pharma GmbH & Co. KG, CNS Diseases Research, 88397 Biberach an der Riss, Germany.
authors: Mareike
authors: M
authors: Caesar
authors: Susanne
authors: S
authors: Zach
authors: Coby B
authors: CB
authors: Carlson
authors: Kathrin
authors: K
authors: Brockmann
authors: Thomas
authors: T
authors: Gasser
authors: Frank
authors: F
authors: Gillardon
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D051379:Mice; D008870:Microtubules / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D041701:Swiss 3T3 Cells
chemical_list: C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases