摘要：SummaryMutations in LRRK2 increase its kinase activity and cause Parkinson's disease. LRRK2 phosphorylates a subset of Rab proteins which allows for their binding to RILPL1. The phospho-Rab/RILPL1 interaction causes deficits in ciliogenesis and interferes with the cohesion of duplicated centrosomes. We show here that centrosomal deficits mediated by pathogenic LRRK2 can also be observed in patient-derived iPS cells, and we have used transiently transfected cell lines to identify the underlying mechanism. The LRRK2-mediated centrosomal cohesion deficits are dependent on both the GTP conformation and phosphorylation status of the Rab proteins. Pathogenic LRRK2 does not displace proteinaceous linker proteins which hold duplicated centrosomes together, but causes the centrosomal displacement of CDK5RAP2, a protein critical for centrosome cohesion. The LRRK2-mediated centrosomal displacement of CDK5RAP2 requires RILPL1 and phospho-Rab proteins, which stably associate with centrosomes. These data provide fundamental information as to how pathogenic LRRK2 alters the normal physiology of a cell.Graphical abstractDisplay OmittedHighlights•The Parkinson's disease kinase LRRK2 causes a centrosomal cohesion deficit•The cohesion deficit depends on the Rab GTP conformation and phosphorylation status•The cohesion deficit is not because of the displacement of centrosomal linker proteins•The deficit is because of CDK5RAP2 displacement mediated by the RILPL1/phospho-Rab8/10 complexBiological sciences; Neuroscience; Cellular neuroscience; Cell biology; Functional aspects of cell biology
