Stoica, R;
Paillusson, S;
Gomez-Suaga, P;
Mitchell, JC;
Lau, DHW;
Gray, EH;
Sancho, RM;
... Miller, CCJ; + view all
(2016)
ALS/FTD-associated FUS activates GSK-3 to disrupt the VAPB-PTPIP51 interaction and ER-mitochondria associations.
EMBO reports
, 17
(9)
pp. 1326-1342.
10.15252/embr.201541726.
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Abstract
Defective FUS metabolism is strongly associated with amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD), but the mechanisms linking FUS to disease are not properly understood. However, many of the functions disrupted in ALS/FTD are regulated by signalling between the endoplasmic reticulum (ER) and mitochondria. This signalling is facilitated by close physical associations between the two organelles that are mediated by binding of the integral ER protein VAPB to the outer mitochondrial membrane protein PTPIP51, which act as molecular scaffolds to tether the two organelles. Here, we show that FUS disrupts the VAPB–PTPIP51 interaction and ER–mitochondria associations. These disruptions are accompanied by perturbation of Ca2+ uptake by mitochondria following its release from ER stores, which is a physiological read‐out of ER–mitochondria contacts. We also demonstrate that mitochondrial ATP production is impaired in FUS‐expressing cells; mitochondrial ATP production is linked to Ca2+ levels. Finally, we demonstrate that the FUS‐induced reductions to ER–mitochondria associations and are linked to activation of glycogen synthase kinase‐3β (GSK‐3β), a kinase already strongly associated with ALS/FTD.
| Type: | Article |
|---|---|
| Title: | ALS/FTD-associated FUS activates GSK-3 to disrupt the VAPB-PTPIP51 interaction and ER-mitochondria associations |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.15252/embr.201541726 |
| Publisher version: | https://doi.org/10.15252/embr.201541726 |
| Language: | English |
| Additional information: | This is an open access article under the terms of the Creative Commons Attribution 4.0 License (https://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
| Keywords: | amyotrophic lateral sclerosis; frontotemporal dementia; glycogen synthase kinase-3b; protein tyrosine phosphatase interacting protein 51; vesicle-associated membrane protein-associated protein B |
| 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 > Department of Neuromuscular Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10065926 |
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