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

Elena Fdez; Jesús Madero-Pérez; Antonio J Lara Ordóñez; Yahaira Naaldijk; Rachel Fasiczka; Ana Aiastui; Javier Ruiz-Martínez; Adolfo López de Munain; Sally A Cowley; Richard Wade-Martins; Sabine Hilfiker

doi:10.1016/j.isci.2022.104476

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

iScience. 2022 May 30;25(6):104476. doi: 10.1016/j.isci.2022.104476. eCollection 2022 Jun 17.

Authors

Elena Fdez¹, Jesús Madero-Pérez¹, Antonio J Lara Ordóñez¹, Yahaira Naaldijk², Rachel Fasiczka², Ana Aiastui^{3

4}, Javier Ruiz-Martínez^{3

5

6}, Adolfo López de Munain^{3

5

6

7}, Sally A Cowley^{8

9}, Richard Wade-Martins^{9

10}, Sabine Hilfiker³

Affiliations

¹ Institute of Parasitology and Biomedicine "López-Neyra", Consejo Superior de Investigaciones Científicas (CSIC), 18016 Granada, Spain.
² Department of Anesthesiology, Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA.
³ CIBERNED (Institute Carlos III), Madrid, Spain.
⁴ Cell Culture Platform, Biodonostia Institute, San Sebastian, Spain.
⁵ Department of Neurology, Hospital Universitario Donostia-OSAKIDETZA, San Sebastian, Spain.
⁶ Neurosciences Area, Biodonostia Institute, San Sebastian, Spain.
⁷ Department of Neurosciences, University of the Basque Country, San Sebastian, Spain.
⁸ Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
⁹ Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
¹⁰ Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.

Abstract

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.

Keywords: Biological sciences; Cell biology; Cellular neuroscience; Functional aspects of cell biology; Neuroscience.

Abstract

Grants and funding