Distinct profiles of LRRK2 activation and Rab GTPase phosphorylation in clinical samples from different PD cohorts
Abstract Despite several advances in the field, pharmacodynamic outcome measures reflective of LRRK2 kinase activity in clinical biofluids remain urgently needed. A variety of targets and approaches have been utilized including assessments of LRRK2 itself (levels, phosphorylation), or its substrates...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-06-01
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| Series: | npj Parkinson's Disease |
| Online Access: | https://doi.org/10.1038/s41531-022-00336-5 |
| _version_ | 1797428269711097856 |
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| author | Lilian Petropoulou-Vathi Athina Simitsi Politymi-Eleni Valkimadi Maria Kedariti Lampros Dimitrakopoulos Christos Koros Dimitra Papadimitriou Alexandros Papadimitriou Leonidas Stefanis Roy N. Alcalay Hardy J. Rideout |
| author_facet | Lilian Petropoulou-Vathi Athina Simitsi Politymi-Eleni Valkimadi Maria Kedariti Lampros Dimitrakopoulos Christos Koros Dimitra Papadimitriou Alexandros Papadimitriou Leonidas Stefanis Roy N. Alcalay Hardy J. Rideout |
| author_sort | Lilian Petropoulou-Vathi |
| collection | DOAJ |
| description | Abstract Despite several advances in the field, pharmacodynamic outcome measures reflective of LRRK2 kinase activity in clinical biofluids remain urgently needed. A variety of targets and approaches have been utilized including assessments of LRRK2 itself (levels, phosphorylation), or its substrates (e.g. Rab10 or other Rab GTPases). We have previously shown that intrinsic kinase activity of LRRK2 isolated from PBMCs of G2019S carriers is elevated, irrespective of disease status. In the present study we find that phosphorylation of Rab10 is also elevated in G2019S carriers, but only those with PD. Additionally, phosphorylation of this substrate is also elevated in two separate idiopathic PD cohorts, but not in carriers of the A53T mutation in α-synuclein. In contrast, Rab29 phosphorylation was specifically reduced in urinary exosomes from A53T and idiopathic PD patients. Taken together, our findings highlight the need for the assessment of multiple complimentary targets for a more comprehensive picture of the disease. |
| first_indexed | 2024-03-09T08:55:37Z |
| format | Article |
| id | doaj.art-e4cbd67941914be9bc6264061c374bf5 |
| institution | Directory Open Access Journal |
| issn | 2373-8057 |
| language | English |
| last_indexed | 2024-03-09T08:55:37Z |
| publishDate | 2022-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Parkinson's Disease |
| spelling | doaj.art-e4cbd67941914be9bc6264061c374bf52023-12-02T13:14:40ZengNature Portfolionpj Parkinson's Disease2373-80572022-06-01811610.1038/s41531-022-00336-5Distinct profiles of LRRK2 activation and Rab GTPase phosphorylation in clinical samples from different PD cohortsLilian Petropoulou-Vathi0Athina Simitsi1Politymi-Eleni Valkimadi2Maria Kedariti3Lampros Dimitrakopoulos4Christos Koros5Dimitra Papadimitriou6Alexandros Papadimitriou7Leonidas Stefanis8Roy N. Alcalay9Hardy J. Rideout10Center for Clinical, Experimental Surgery, and Translational Research, Biomedical Research Foundation of the Academy of AthensDepartment of Neurology, University of Athens Medical SchoolCenter for Clinical, Experimental Surgery, and Translational Research, Biomedical Research Foundation of the Academy of AthensCenter for Clinical, Experimental Surgery, and Translational Research, Biomedical Research Foundation of the Academy of AthensCenter for Clinical, Experimental Surgery, and Translational Research, Biomedical Research Foundation of the Academy of AthensDepartment of Neurology, University of Athens Medical SchoolDepartment of Neurology, Henry Dunant Hospital CentreDepartment of Neurology, Henry Dunant Hospital CentreCenter for Clinical, Experimental Surgery, and Translational Research, Biomedical Research Foundation of the Academy of AthensDepartment of Neurology, Columbia UniversityCenter for Clinical, Experimental Surgery, and Translational Research, Biomedical Research Foundation of the Academy of AthensAbstract Despite several advances in the field, pharmacodynamic outcome measures reflective of LRRK2 kinase activity in clinical biofluids remain urgently needed. A variety of targets and approaches have been utilized including assessments of LRRK2 itself (levels, phosphorylation), or its substrates (e.g. Rab10 or other Rab GTPases). We have previously shown that intrinsic kinase activity of LRRK2 isolated from PBMCs of G2019S carriers is elevated, irrespective of disease status. In the present study we find that phosphorylation of Rab10 is also elevated in G2019S carriers, but only those with PD. Additionally, phosphorylation of this substrate is also elevated in two separate idiopathic PD cohorts, but not in carriers of the A53T mutation in α-synuclein. In contrast, Rab29 phosphorylation was specifically reduced in urinary exosomes from A53T and idiopathic PD patients. Taken together, our findings highlight the need for the assessment of multiple complimentary targets for a more comprehensive picture of the disease.https://doi.org/10.1038/s41531-022-00336-5 |
| spellingShingle | Lilian Petropoulou-Vathi Athina Simitsi Politymi-Eleni Valkimadi Maria Kedariti Lampros Dimitrakopoulos Christos Koros Dimitra Papadimitriou Alexandros Papadimitriou Leonidas Stefanis Roy N. Alcalay Hardy J. Rideout Distinct profiles of LRRK2 activation and Rab GTPase phosphorylation in clinical samples from different PD cohorts npj Parkinson's Disease |
| title | Distinct profiles of LRRK2 activation and Rab GTPase phosphorylation in clinical samples from different PD cohorts |
| title_full | Distinct profiles of LRRK2 activation and Rab GTPase phosphorylation in clinical samples from different PD cohorts |
| title_fullStr | Distinct profiles of LRRK2 activation and Rab GTPase phosphorylation in clinical samples from different PD cohorts |
| title_full_unstemmed | Distinct profiles of LRRK2 activation and Rab GTPase phosphorylation in clinical samples from different PD cohorts |
| title_short | Distinct profiles of LRRK2 activation and Rab GTPase phosphorylation in clinical samples from different PD cohorts |
| title_sort | distinct profiles of lrrk2 activation and rab gtpase phosphorylation in clinical samples from different pd cohorts |
| url | https://doi.org/10.1038/s41531-022-00336-5 |
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