Herbst, S;
Campbell, P;
Harvey, J;
Bernard, EM;
Papayannopoulos, V;
Wood, NW;
Morris, HR;
(2020)
LRRK2 activation controls the repair of damaged endomembranes in macrophages.
The EMBO Journal
, Article e104494. 10.15252/embj.2020104494.
(In press).
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Abstract
Cells respond to endolysosome damage by either repairing the damage or targeting damaged endolysosomes for degradation via lysophagy. However, the signals regulating the decision for repair or lysophagy are poorly characterised. Here, we show that the Parkinson’s disease (PD)-related kinase LRRK2 is activated in macrophages by pathogen- or sterile-induced endomembrane damage. LRRK2 recruits the Rab GTPase Rab8A to damaged endolysosomes as well as the ESCRT-III component CHMP4B, thereby favouring ESCRT-mediated repair. Conversely, in the absence of LRRK2 and Rab8A, damaged endolysosomes are targeted to lysophagy. These observations are recapitulated in macrophages from PD patients where pathogenic LRRK2 gainof-function mutations result in the accumulation of endolysosomes which are positive for the membrane damage marker Galectin-3. Altogether, this work indicates that LRRK2 regulates endolysosomal homeostasis by controlling the balance between membrane repair and organelle replacement, uncovering an unexpected function for LRRK2, and providing a new link between membrane damage and PD
| Type: | Article |
|---|---|
| Title: | LRRK2 activation controls the repair of damaged endomembranes in macrophages |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.15252/embj.2020104494 |
| Publisher version: | https://doi.org/10.15252/embj.2020104494 |
| Language: | English |
| Additional information: | This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited http://creativecommons.org/licenses/by/4.0/ |
| Keywords: | LRRK2, Parkinson's disease, endolysosomal damage, lysosomes, tuberculosis |
| UCL classification: | UCL 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 |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10105927 |
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