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Pharmacological LRRK2 kinase inhibition induces LRRK2 protein destabilization and proteasomal degradation
Leucine-rich repeat kinase 2 (LRRK2) kinase activity is increased in several pathogenic mutations, including the most common mutation, G2019S, and is known to play a role in Parkinson’s disease (PD) pathobiology. This has stimulated the development of potent, selective LRRK2 kinase inhibitors as one...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5034242/ https://www.ncbi.nlm.nih.gov/pubmed/27658356 http://dx.doi.org/10.1038/srep33897 |
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author | Lobbestael, E. Civiero, L. De Wit, T. Taymans, J.-M. Greggio, E. Baekelandt, V. |
author_facet | Lobbestael, E. Civiero, L. De Wit, T. Taymans, J.-M. Greggio, E. Baekelandt, V. |
author_sort | Lobbestael, E. |
collection | PubMed |
description | Leucine-rich repeat kinase 2 (LRRK2) kinase activity is increased in several pathogenic mutations, including the most common mutation, G2019S, and is known to play a role in Parkinson’s disease (PD) pathobiology. This has stimulated the development of potent, selective LRRK2 kinase inhibitors as one of the most prevailing disease-modifying therapeutic PD strategies. Although several lines of evidence support beneficial effects of LRRK2 kinase inhibitors, many questions need to be answered before clinical applications can be envisaged. Using six different LRRK2 kinase inhibitors, we show that LRRK2 kinase inhibition induces LRRK2 dephosphorylation and can reduce LRRK2 protein levels of overexpressed wild type and G2019S, but not A2016T or K1906M, LRRK2 as well as endogenous LRRK2 in mouse brain, lung and kidney. The inhibitor-induced reduction in LRRK2 levels could be reversed by proteasomal inhibition, but not by lysosomal inhibition, while mRNA levels remained unaffected. In addition, using LRRK2 S910A and S935A phosphorylation mutants, we show that dephosphorylation of these sites is not required for LRRK2 degradation. Increasing our insight in the molecular and cellular consequences of LRRK2 kinase inhibition will be crucial in the further development of LRRK2-based PD therapies. |
format | Online Article Text |
id | pubmed-5034242 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-50342422016-09-29 Pharmacological LRRK2 kinase inhibition induces LRRK2 protein destabilization and proteasomal degradation Lobbestael, E. Civiero, L. De Wit, T. Taymans, J.-M. Greggio, E. Baekelandt, V. Sci Rep Article Leucine-rich repeat kinase 2 (LRRK2) kinase activity is increased in several pathogenic mutations, including the most common mutation, G2019S, and is known to play a role in Parkinson’s disease (PD) pathobiology. This has stimulated the development of potent, selective LRRK2 kinase inhibitors as one of the most prevailing disease-modifying therapeutic PD strategies. Although several lines of evidence support beneficial effects of LRRK2 kinase inhibitors, many questions need to be answered before clinical applications can be envisaged. Using six different LRRK2 kinase inhibitors, we show that LRRK2 kinase inhibition induces LRRK2 dephosphorylation and can reduce LRRK2 protein levels of overexpressed wild type and G2019S, but not A2016T or K1906M, LRRK2 as well as endogenous LRRK2 in mouse brain, lung and kidney. The inhibitor-induced reduction in LRRK2 levels could be reversed by proteasomal inhibition, but not by lysosomal inhibition, while mRNA levels remained unaffected. In addition, using LRRK2 S910A and S935A phosphorylation mutants, we show that dephosphorylation of these sites is not required for LRRK2 degradation. Increasing our insight in the molecular and cellular consequences of LRRK2 kinase inhibition will be crucial in the further development of LRRK2-based PD therapies. Nature Publishing Group 2016-09-23 /pmc/articles/PMC5034242/ /pubmed/27658356 http://dx.doi.org/10.1038/srep33897 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Lobbestael, E. Civiero, L. De Wit, T. Taymans, J.-M. Greggio, E. Baekelandt, V. Pharmacological LRRK2 kinase inhibition induces LRRK2 protein destabilization and proteasomal degradation |
title | Pharmacological LRRK2 kinase inhibition induces LRRK2 protein destabilization and proteasomal degradation |
title_full | Pharmacological LRRK2 kinase inhibition induces LRRK2 protein destabilization and proteasomal degradation |
title_fullStr | Pharmacological LRRK2 kinase inhibition induces LRRK2 protein destabilization and proteasomal degradation |
title_full_unstemmed | Pharmacological LRRK2 kinase inhibition induces LRRK2 protein destabilization and proteasomal degradation |
title_short | Pharmacological LRRK2 kinase inhibition induces LRRK2 protein destabilization and proteasomal degradation |
title_sort | pharmacological lrrk2 kinase inhibition induces lrrk2 protein destabilization and proteasomal degradation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5034242/ https://www.ncbi.nlm.nih.gov/pubmed/27658356 http://dx.doi.org/10.1038/srep33897 |
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