Impact of Type II LRRK2 inhibitors on signaling and mitophagy
| Autor: | Ian G. Ganley, Anna Tasegian, Alastair D. Reith, François Singh, Dario R. Alessi |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Indazoles
kinase kinase inhibitor Neutrophils Pyridines Mutant medicine.disease_cause Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 Transfection Biochemistry Dephosphorylation Gene Knockout Techniques Mice Parkinsons disease Mitophagy medicine leucine rich repeat kinase Animals Humans Phosphorylation Molecular Biology Protein Kinase Inhibitors Research Articles Mutation Post-Translational Modifications Kinase Chemistry Pharmacology & Toxicology Imidazoles Parkinson Disease Cell Biology Fibroblasts LRRK2 Signaling Cell biology nervous system diseases Mice Inbred C57BL Pyridazines HEK293 Cells Pyrimidines Protein kinase domain Benzamides Quinolines Pyrazoles Rab GTPase HeLa Cells Signal Transduction |
| Zdroj: | Biochemical Journal |
| ISSN: | 1470-8728 0264-6021 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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