Pathogenic LRRK2 regulates centrosome cohesion via Rab10/RILPL1-mediated CDK5RAP2 displacement

iScience

卷:25

Javier Ruiz-Martínez¹  Sally A. Cowley²  Richard Wade-Martins³  Adolfo López de Munain⁴  Ana Aiastui⁴  Sabine Hilfiker⁴  Yahaira Naaldijk⁵  Rachel Fasiczka⁵  Elena Fdez⁶  Jesús Madero-Pérez⁶  Antonio J. Lara Ordóñez⁶ 

[1] Cell Culture Platform, Biodonostia Institute, San Sebastian, Spain;

[2] Department of Neurology, Hospital Universitario Donostia-OSAKIDETZA, San Sebastian, Spain;

[3] Neurosciences Area, Biodonostia Institute, San Sebastian, Spain;

[4] CIBERNED (Institute Carlos III), Madrid, Spain;

[5] Department of Anesthesiology, Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA;

[6] Institute of Parasitology and Biomedicine ''López-Neyra'', Consejo Superior de Investigaciones Científicas (CSIC), 18016 Granada, Spain;

关键词: Biological sciences;    Neuroscience;    Cellular neuroscience;    Cell biology;    Functional aspects of cell biology;   

DOI  :  

来源: DOAJ

【 摘 要 】

Summary: Mutations 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.

【 授权许可】

Unknown