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Impact of Type II LRRK2 inhibitors on signaling and mitophagy
Much effort has been devoted to the development of selective inhibitors of the LRRK2 as a potential treatment for LRRK2 driven Parkinson's disease. In this study, we first compare the properties of Type I (GSK3357679A and MLi-2) and Type II (GZD-824, Rebastinib and Ponatinib) kinase inhibitors...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Portland Press Ltd.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8589421/ https://www.ncbi.nlm.nih.gov/pubmed/34515301 http://dx.doi.org/10.1042/BCJ20210375 |
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author | Tasegian, Anna Singh, Francois Ganley, Ian G. Reith, Alastair D. Alessi, Dario R. |
author_facet | Tasegian, Anna Singh, Francois Ganley, Ian G. Reith, Alastair D. Alessi, Dario R. |
author_sort | Tasegian, Anna |
collection | PubMed |
description | Much effort has been devoted to the development of selective inhibitors of the LRRK2 as a potential treatment for LRRK2 driven Parkinson's disease. In this study, we first compare the properties of Type I (GSK3357679A and MLi-2) and Type II (GZD-824, Rebastinib and Ponatinib) kinase inhibitors that bind to the closed or open conformations of the LRRK2 kinase domain, respectively. We show that Type I and Type II inhibitors suppress phosphorylation of Rab10 and Rab12, key physiological substrates of LRRK2 and also promote mitophagy, a process suppressed by LRRK2. Type II inhibitors also display higher potency towards wild-type LRRK2 compared with pathogenic mutants. Unexpectedly, we find that Type II inhibitors, in contrast with Type I compounds, fail to induce dephosphorylation of a set of well-studied LRRK2 biomarker phosphorylation sites at the N-terminal region of LRRK2, including Ser935. These findings emphasize that the biomarker phosphorylation sites on LRRK2 are likely reporting on the open vs closed conformation of LRRK2 kinase and that only inhibitors which stabilize the closed conformation induce dephosphorylation of these biomarker sites. Finally, we demonstrate that the LRRK2[A2016T] mutant which is resistant to MLi-2 Type 1 inhibitor, also induces resistance to GZD-824 and Rebastinib suggesting this mutation could be exploited to distinguish off target effects of Type II inhibitors. Our observations provide a framework of knowledge to aid with the development of more selective Type II LRRK2 inhibitors. |
format | Online Article Text |
id | pubmed-8589421 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Portland Press Ltd. |
record_format | MEDLINE/PubMed |
spelling | pubmed-85894212021-11-18 Impact of Type II LRRK2 inhibitors on signaling and mitophagy Tasegian, Anna Singh, Francois Ganley, Ian G. Reith, Alastair D. Alessi, Dario R. Biochem J Signaling Much effort has been devoted to the development of selective inhibitors of the LRRK2 as a potential treatment for LRRK2 driven Parkinson's disease. In this study, we first compare the properties of Type I (GSK3357679A and MLi-2) and Type II (GZD-824, Rebastinib and Ponatinib) kinase inhibitors that bind to the closed or open conformations of the LRRK2 kinase domain, respectively. We show that Type I and Type II inhibitors suppress phosphorylation of Rab10 and Rab12, key physiological substrates of LRRK2 and also promote mitophagy, a process suppressed by LRRK2. Type II inhibitors also display higher potency towards wild-type LRRK2 compared with pathogenic mutants. Unexpectedly, we find that Type II inhibitors, in contrast with Type I compounds, fail to induce dephosphorylation of a set of well-studied LRRK2 biomarker phosphorylation sites at the N-terminal region of LRRK2, including Ser935. These findings emphasize that the biomarker phosphorylation sites on LRRK2 are likely reporting on the open vs closed conformation of LRRK2 kinase and that only inhibitors which stabilize the closed conformation induce dephosphorylation of these biomarker sites. Finally, we demonstrate that the LRRK2[A2016T] mutant which is resistant to MLi-2 Type 1 inhibitor, also induces resistance to GZD-824 and Rebastinib suggesting this mutation could be exploited to distinguish off target effects of Type II inhibitors. Our observations provide a framework of knowledge to aid with the development of more selective Type II LRRK2 inhibitors. Portland Press Ltd. 2021-10-15 2021-10-06 /pmc/articles/PMC8589421/ /pubmed/34515301 http://dx.doi.org/10.1042/BCJ20210375 Text en © 2021 The Author(s) https://creativecommons.org/licenses/by/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) (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Signaling Tasegian, Anna Singh, Francois Ganley, Ian G. Reith, Alastair D. Alessi, Dario R. Impact of Type II LRRK2 inhibitors on signaling and mitophagy |
title | Impact of Type II LRRK2 inhibitors on signaling and mitophagy |
title_full | Impact of Type II LRRK2 inhibitors on signaling and mitophagy |
title_fullStr | Impact of Type II LRRK2 inhibitors on signaling and mitophagy |
title_full_unstemmed | Impact of Type II LRRK2 inhibitors on signaling and mitophagy |
title_short | Impact of Type II LRRK2 inhibitors on signaling and mitophagy |
title_sort | impact of type ii lrrk2 inhibitors on signaling and mitophagy |
topic | Signaling |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8589421/ https://www.ncbi.nlm.nih.gov/pubmed/34515301 http://dx.doi.org/10.1042/BCJ20210375 |
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