Centrosomal cohesion deficits as cellular biomarker in lymphoblastoid cell lines from LRRK2 Parkinson's disease patients
| Autor: | Alain Destée, Sabine Hilfiker, Elena Fdez, Thomas Comptdaer, Jean-Marc Taymans, Eugénie Mutez, Alexandre Kreisler, Belén Fernández, Laurine Vandewynckel, Marie-Christine Chartier-Harlin, Coline Leghay, Luc Defebvre, Séverine Bleuse, Clémence Simonin, Antonio Ordóñez |
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| Přispěvatelé: | Michael J. Fox Foundation for Parkinson's Research, European Commission, Ministerio de Ciencia, Innovación y Universidades (España), Université de Lille |
| Rok vydání: | 2019 |
| Předmět: |
Adult
Male Parkinson's disease Cell Leucine-rich repeat kinase Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 Biochemistry Molecular Bases of Health & Disease 03 medical and health sciences Protein phosphorylation 0302 clinical medicine Cell Line Tumor Rab protein Centrosome cohesion medicine Humans Phosphorylation Kinase activity Molecular Biology Research Articles Diagnostics & Biomarkers Aged 030304 developmental biology Centrosome 0303 health sciences Post-Translational Modifications business.industry Kinase Parkinson Disease Cell Biology Middle Aged medicine.disease LRRK2 Signaling nervous system diseases medicine.anatomical_structure Leukocytes Mononuclear Cancer research Biomarker (medicine) Female business Biomarkers 030217 neurology & neurosurgery |
| Zdroj: | Biochemical Journal Digital.CSIC. Repositorio Institucional del CSIC instname |
| ISSN: | 1470-8728 0264-6021 |
| Popis: | Leucine-rich repeat kinase 2 (LRRK2) is a promising therapeutic target for the treatment of Parkinson's disease (PD), and orally bioavailable, brain penetrant and highly potent LRRK2 kinase inhibitors are in early stages of clinical testing. Detection of LRRK2 phosphorylation, as well as phosphorylation of Rab10, a LRRK2 kinase substrate, have been proposed as target engagement biomarkers for LRRK2 inhibitor clinical trials. However, these readouts do not seem able to stratify patients based on enhanced LRRK2 kinase activity. Here, we describe a robust cell biological assay based on centrosomal cohesion alterations which were observed in peripheral blood mononuclear cellderived lymphoblastoid cell lines (LCLs) from patients with G2019S LRRK2 mutations as compared with healthy controls, and could also be detected in a subset of sporadic PD patient samples. We suggest that LCLs may be a valuable resource for LRRK2 research, and that determination of centrosomal cohesion deficits may assist in the stratification of a subset of sporadic PD patients. This work was supported by funding from the Michael J. Fox Foundation for Parkinson's Research (U.S.A.), FEDER, the Spanish Ministry of Science, Innovation and Universities (SAF2017-89402-R), and by the French Ministry of Health's PHRC program (CONVERGENCE 2008-A00219-42), the University of Lille, Inserm and the Lille University Hospital. |
| Databáze: | OpenAIRE |
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