LRRK2 kinase inhibition, a potential Parkinson’s disease therapy, induces LRRK2 protein destabilization and proteasomal degradation

Abstract

Event Abstract Back to Event LRRK2 kinase inhibition, a potential Parkinson’s disease therapy, induces LRRK2 protein destabilization and proteasomal degradation Evy Lobbestael1*, Laura Civiero2, Tina De Wit1, Jean-Marc Taymans3, Elisa Greggio2 and Veerle Baekelandt1 1 KU Leuven, Neurosciences, Belgium 2 University of Padova, Italy 3 INSERM-CHRU de Lille-Université de Lille, France Leucine-rich repeat kinase 2 (LRRK2) kinase activity is increased in several pathogenic mutations, including the most common mutation, G2019S, and plays a role in Parkinson’s disease (PD) pathobiology. LRRK2 kinase inhibitors are currently one of the most prevailing disease-modifying therapeutic PD strategies and although several lines of evidence support beneficial effects, many questions need to be answered before clinical applications can be envisaged. We aimed to gain insight in the LRRK2 kinase inhibitor-induced reduction in LRRK2 protein levels. We used six different LRRK2 kinase inhibitors administered to mice, primary cultures and cell lines and monitored LRRK2 (phosphorylation) levels via immunoblotting at different time points. 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 and primary astrocytes. This effect could be reversed by proteasomal inhibition, but not by lysosomal inhibition, while mRNA levels remained unaffected. Using LRRK2 S910A and S935A phosphorylation mutants, we show that dephosphorylation of these sites is not required for LRRK2 degradation. Interestingly, a truncated form of LRRK2, detected in mouse kidney, is dephosphorylated upon LRRK2 kinase inhibition, but not destabilized. In conclusion, we show that LRRK2 kinase inhibitor-induced LRRK2 destabilization is mediated by proteasomal degradation. This effect appears to be cell type specific and is not (only) dependent on dephosphorylation at LRRK2 S910 and S935. Increasing our insight in the molecular consequences of LRRK2 kinase inhibition will be crucial in the development of LRRK2-based PD therapies. Keywords: LRRK2, Kinase inhibition, Parkinson's disease, therapy, proteasomal degradation Conference: 12th National Congress of the Belgian Society for Neuroscience, Gent, Belgium, 22 May - 22 May, 2017. Presentation Type: Oral Presentation Topic: Disorders of the Nervous System Citation: Lobbestael E, Civiero L, De Wit T, Taymans J, Greggio E and Baekelandt V (2019). LRRK2 kinase inhibition, a potential Parkinson’s disease therapy, induces LRRK2 protein destabilization and proteasomal degradation. Front. Neurosci. Conference Abstract: 12th National Congress of the Belgian Society for Neuroscience. doi: 10.3389/conf.fnins.2017.94.00100 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 21 Apr 2017; Published Online: 25 Jan 2019. * Correspondence: Dr. Evy Lobbestael, KU Leuven, Neurosciences, Leuven, Belgium, evy.lobbestael@kuleuven.be Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Evy Lobbestael Laura Civiero Tina De Wit Jean-Marc Taymans Elisa Greggio Veerle Baekelandt Google Evy Lobbestael Laura Civiero Tina De Wit Jean-Marc Taymans Elisa Greggio Veerle Baekelandt Google Scholar Evy Lobbestael Laura Civiero Tina De Wit Jean-Marc Taymans Elisa Greggio Veerle Baekelandt PubMed Evy Lobbestael Laura Civiero Tina De Wit Jean-Marc Taymans Elisa Greggio Veerle Baekelandt Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.