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Centrosomal cohesion deficits as cellular biomarker in lymphoblastoid cell lines from LRRK2 Parkinson's disease patients
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 phosph...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Portland Press Ltd.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6792036/ https://www.ncbi.nlm.nih.gov/pubmed/31527116 http://dx.doi.org/10.1042/BCJ20190315 |
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author | Fernández, Belén Lara Ordóñez, Antonio Jesús Fdez, Elena Mutez, Eugénie Comptdaer, Thomas Leghay, Coline Kreisler, Alexandre Simonin, Clémence Vandewynckel, Laurine Defebvre, Luc Destée, Alain Bleuse, Séverine Taymans, Jean-Marc Chartier-Harlin, Marie-Christine Hilfiker, Sabine |
author_facet | Fernández, Belén Lara Ordóñez, Antonio Jesús Fdez, Elena Mutez, Eugénie Comptdaer, Thomas Leghay, Coline Kreisler, Alexandre Simonin, Clémence Vandewynckel, Laurine Defebvre, Luc Destée, Alain Bleuse, Séverine Taymans, Jean-Marc Chartier-Harlin, Marie-Christine Hilfiker, Sabine |
author_sort | Fernández, Belén |
collection | PubMed |
description | 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 cell-derived 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. |
format | Online Article Text |
id | pubmed-6792036 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Portland Press Ltd. |
record_format | MEDLINE/PubMed |
spelling | pubmed-67920362019-10-24 Centrosomal cohesion deficits as cellular biomarker in lymphoblastoid cell lines from LRRK2 Parkinson's disease patients Fernández, Belén Lara Ordóñez, Antonio Jesús Fdez, Elena Mutez, Eugénie Comptdaer, Thomas Leghay, Coline Kreisler, Alexandre Simonin, Clémence Vandewynckel, Laurine Defebvre, Luc Destée, Alain Bleuse, Séverine Taymans, Jean-Marc Chartier-Harlin, Marie-Christine Hilfiker, Sabine Biochem J Research Articles 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 cell-derived 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. Portland Press Ltd. 2019-10-15 2019-10-11 /pmc/articles/PMC6792036/ /pubmed/31527116 http://dx.doi.org/10.1042/BCJ20190315 Text en © 2019 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Research Articles Fernández, Belén Lara Ordóñez, Antonio Jesús Fdez, Elena Mutez, Eugénie Comptdaer, Thomas Leghay, Coline Kreisler, Alexandre Simonin, Clémence Vandewynckel, Laurine Defebvre, Luc Destée, Alain Bleuse, Séverine Taymans, Jean-Marc Chartier-Harlin, Marie-Christine Hilfiker, Sabine Centrosomal cohesion deficits as cellular biomarker in lymphoblastoid cell lines from LRRK2 Parkinson's disease patients |
title | Centrosomal cohesion deficits as cellular biomarker in lymphoblastoid cell lines from LRRK2 Parkinson's disease patients |
title_full | Centrosomal cohesion deficits as cellular biomarker in lymphoblastoid cell lines from LRRK2 Parkinson's disease patients |
title_fullStr | Centrosomal cohesion deficits as cellular biomarker in lymphoblastoid cell lines from LRRK2 Parkinson's disease patients |
title_full_unstemmed | Centrosomal cohesion deficits as cellular biomarker in lymphoblastoid cell lines from LRRK2 Parkinson's disease patients |
title_short | Centrosomal cohesion deficits as cellular biomarker in lymphoblastoid cell lines from LRRK2 Parkinson's disease patients |
title_sort | centrosomal cohesion deficits as cellular biomarker in lymphoblastoid cell lines from lrrk2 parkinson's disease patients |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6792036/ https://www.ncbi.nlm.nih.gov/pubmed/31527116 http://dx.doi.org/10.1042/BCJ20190315 |
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