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Inhibition of LRRK2 kinase activity stimulates macroautophagy.

Manzoni, C; Mamais, A; Dihanich, S; Abeti, R; Soutar, MP; Plun-Favreau, H; Giunti, P; ... Lewis, PA; + view all (2013) Inhibition of LRRK2 kinase activity stimulates macroautophagy. Biochim Biophys Acta , 1833 (12) pp. 2900-2910. 10.1016/j.bbamcr.2013.07.020. Green open access

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Abstract

Leucine Rich Repeat Kinase 2 (LRRK2) is one of the most important genetic contributors to Parkinson's disease. LRRK2 has been implicated in a number of cellular processes, including macroautophagy. To test whether LRRK2 has a role in regulating autophagy, a specific inhibitor of the kinase activity of LRRK2 was applied to human neuroglioma cells and downstream readouts of autophagy examined. The resulting data demonstrate that inhibition of LRRK2 kinase activity stimulates macroautophagy in the absence of any alteration in the translational targets of mTORC1, suggesting that LRRK2 regulates autophagic vesicle formation independent of canonical mTORC1 signaling. This study represents the first pharmacological dissection of the role LRRK2 plays in the autophagy/lysosomal pathway, emphasizing the importance of this pathway as a marker for LRRK2 physiological function. Moreover it highlights the need to dissect autophagy and lysosomal activities in the context of LRRK2 related pathologies with the final aim of understand their aetiology and identify specific target for disease modifying therapies in patients.

Type: Article
Title: Inhibition of LRRK2 kinase activity stimulates macroautophagy.
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.bbamcr.2013.07.020
Publisher version: http://dx.doi.org/10.1016/j.bbamcr.2013.07.020
Additional information: © 2013 The Authors. Published by Elsevier B.V. All rights reserved. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords: C-terminal of ROC domain, COR, DMSO, DPBS, Dimethylsulfoxide, Dulbecco’s phosphate buffered saline, EDTA, LC3, LRRK2, Leucine Rich Repeat Kinase 2, Parkinson’s disease, ROC, Ras of Complex Proteins, SDS, WIPI2, ethylene di-ammonium tetra acetic acid, mTOR, macroautophagy, mammalian target of rapamycin, p62, sodium dodecyl sulphate
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
URI: http://discovery.ucl.ac.uk/id/eprint/1401868
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