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Exosome markers of LRRK2 kinase inhibition

Hyper-activated LRRK2 is linked to Parkinson’s disease susceptibility and progression. Quantitative measures of LRRK2 inhibition, especially in the brain, maybe critical in the development of successful LRRK2-targeting therapeutics. In this study, two different brain-penetrant and selective LRRK2 sm...

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Autores principales: Wang, Shijie, Kelly, Kaela, Brotchie, Jonathan M., Koprich, James B., West, Andrew B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666125/
https://www.ncbi.nlm.nih.gov/pubmed/33298972
http://dx.doi.org/10.1038/s41531-020-00138-7
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author Wang, Shijie
Kelly, Kaela
Brotchie, Jonathan M.
Koprich, James B.
West, Andrew B.
author_facet Wang, Shijie
Kelly, Kaela
Brotchie, Jonathan M.
Koprich, James B.
West, Andrew B.
author_sort Wang, Shijie
collection PubMed
description Hyper-activated LRRK2 is linked to Parkinson’s disease susceptibility and progression. Quantitative measures of LRRK2 inhibition, especially in the brain, maybe critical in the development of successful LRRK2-targeting therapeutics. In this study, two different brain-penetrant and selective LRRK2 small-molecule kinase inhibitors (PFE-360 and MLi2) were orally administered to groups of cynomolgus macaques. Proposed pharmacodynamic markers in exosomes from urine and cerebrospinal fluid (CSF) were compared to established markers in peripheral blood mononuclear cells (PBMCs). LRRK2 kinase inhibition led to reductions in exosome-LRRK2 protein and the LRRK2-substrate pT73-Rab10 in urine, as well as reduced exosome-LRRK2 and autophosphorylated pS1292-LRRK2 protein in CSF. We propose orthogonal markers for LRRK2 inhibition in urine and CSF can be used in combination with blood markers to non-invasively monitor the potency of LRRK2-targeting therapeutics.
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spelling pubmed-76661252020-11-16 Exosome markers of LRRK2 kinase inhibition Wang, Shijie Kelly, Kaela Brotchie, Jonathan M. Koprich, James B. West, Andrew B. NPJ Parkinsons Dis Article Hyper-activated LRRK2 is linked to Parkinson’s disease susceptibility and progression. Quantitative measures of LRRK2 inhibition, especially in the brain, maybe critical in the development of successful LRRK2-targeting therapeutics. In this study, two different brain-penetrant and selective LRRK2 small-molecule kinase inhibitors (PFE-360 and MLi2) were orally administered to groups of cynomolgus macaques. Proposed pharmacodynamic markers in exosomes from urine and cerebrospinal fluid (CSF) were compared to established markers in peripheral blood mononuclear cells (PBMCs). LRRK2 kinase inhibition led to reductions in exosome-LRRK2 protein and the LRRK2-substrate pT73-Rab10 in urine, as well as reduced exosome-LRRK2 and autophosphorylated pS1292-LRRK2 protein in CSF. We propose orthogonal markers for LRRK2 inhibition in urine and CSF can be used in combination with blood markers to non-invasively monitor the potency of LRRK2-targeting therapeutics. Nature Publishing Group UK 2020-11-13 /pmc/articles/PMC7666125/ /pubmed/33298972 http://dx.doi.org/10.1038/s41531-020-00138-7 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Wang, Shijie
Kelly, Kaela
Brotchie, Jonathan M.
Koprich, James B.
West, Andrew B.
Exosome markers of LRRK2 kinase inhibition
title Exosome markers of LRRK2 kinase inhibition
title_full Exosome markers of LRRK2 kinase inhibition
title_fullStr Exosome markers of LRRK2 kinase inhibition
title_full_unstemmed Exosome markers of LRRK2 kinase inhibition
title_short Exosome markers of LRRK2 kinase inhibition
title_sort exosome markers of lrrk2 kinase inhibition
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666125/
https://www.ncbi.nlm.nih.gov/pubmed/33298972
http://dx.doi.org/10.1038/s41531-020-00138-7
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