Pathogenic LRRK2 regulates centrosome cohesion via Rab10/RILPL1-mediated CDK5RAP2 displacement
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 centr...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-06-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004222007477 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Elena Fdez |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T21:49:51Z |
| format | Article |
| id | doaj.art-3d22d94d6d3d44799ee321641eb2a4fb |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-04-13T21:49:51Z |
| publishDate | 2022-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-3d22d94d6d3d44799ee321641eb2a4fb2022-12-22T02:28:27ZengElsevieriScience2589-00422022-06-01256104476Pathogenic LRRK2 regulates centrosome cohesion via Rab10/RILPL1-mediated CDK5RAP2 displacementElena Fdez0Jesús Madero-Pérez1Antonio J. Lara Ordóñez2Yahaira Naaldijk3Rachel Fasiczka4Ana Aiastui5Javier Ruiz-Martínez6Adolfo López de Munain7Sally A. Cowley8Richard Wade-Martins9Sabine Hilfiker10Institute of Parasitology and Biomedicine ''López-Neyra'', Consejo Superior de Investigaciones Científicas (CSIC), 18016 Granada, SpainInstitute of Parasitology and Biomedicine ''López-Neyra'', Consejo Superior de Investigaciones Científicas (CSIC), 18016 Granada, SpainInstitute of Parasitology and Biomedicine ''López-Neyra'', Consejo Superior de Investigaciones Científicas (CSIC), 18016 Granada, SpainDepartment of Anesthesiology, Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USADepartment of Anesthesiology, Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USACIBERNED (Institute Carlos III), Madrid, Spain; Cell Culture Platform, Biodonostia Institute, San Sebastian, SpainCIBERNED (Institute Carlos III), Madrid, Spain; Department of Neurology, Hospital Universitario Donostia-OSAKIDETZA, San Sebastian, Spain; Neurosciences Area, Biodonostia Institute, San Sebastian, SpainCIBERNED (Institute Carlos III), Madrid, Spain; Department of Neurology, Hospital Universitario Donostia-OSAKIDETZA, San Sebastian, Spain; Neurosciences Area, Biodonostia Institute, San Sebastian, Spain; Department of Neurosciences, University of the Basque Country, San Sebastian, SpainSir William Dunn School of Pathology, University of Oxford, Oxford, UK; Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UKOxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UKCIBERNED (Institute Carlos III), Madrid, Spain; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2589004222007477Biological sciencesNeuroscienceCellular neuroscienceCell biologyFunctional aspects of cell biology |
| spellingShingle | 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 Pathogenic LRRK2 regulates centrosome cohesion via Rab10/RILPL1-mediated CDK5RAP2 displacement iScience Biological sciences Neuroscience Cellular neuroscience Cell biology Functional aspects of cell biology |
| title | Pathogenic LRRK2 regulates centrosome cohesion via Rab10/RILPL1-mediated CDK5RAP2 displacement |
| title_full | Pathogenic LRRK2 regulates centrosome cohesion via Rab10/RILPL1-mediated CDK5RAP2 displacement |
| title_fullStr | Pathogenic LRRK2 regulates centrosome cohesion via Rab10/RILPL1-mediated CDK5RAP2 displacement |
| title_full_unstemmed | Pathogenic LRRK2 regulates centrosome cohesion via Rab10/RILPL1-mediated CDK5RAP2 displacement |
| title_short | Pathogenic LRRK2 regulates centrosome cohesion via Rab10/RILPL1-mediated CDK5RAP2 displacement |
| title_sort | pathogenic lrrk2 regulates centrosome cohesion via rab10 rilpl1 mediated cdk5rap2 displacement |
| topic | Biological sciences Neuroscience Cellular neuroscience Cell biology Functional aspects of cell biology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004222007477 |
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