ALS/FTD-associated FUS activates GSK-3β to disrupt the VAPB-PTPIP51 interaction and ER-mitochondria associations.

Patricia Gomez‐Suaga,Christopher Cj Miller,Jacqueline C Mitchell,Christopher E Shaw,Emma H Gray,Diane P Hanger,Kurt J De Vos,Rosa M Sancho,Sébastien Paillusson,Gema Vizcay‐Barrena,Wendy Noble,Radu Stoica,Dawn Hw Lau

doi:10.15252/embr.201541726

Patricia Gomez‐Suaga, Christopher Cj Miller + Show 11 more

Open Access

https://doi.org/10.15252/embr.201541726

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Journal: EMBO reports	Publication Date: Jul 14, 2016
Citations: 264	License type: CC BY 4.0

Affiliation: King's College London

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.

Highlights

Defective fused in sarcoma (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
Transfection of FUS did not lead to changes in the expression of the endoplasmic reticulum (ER)–mitochondria tethering proteins vesicle-associated membrane protein-associated protein B (VAPB) or protein tyrosine phosphatase interacting protein 51 (PTPIP51), or mitofusin-2, which has been proposed as a further ER–mitochondria tether [40] (Fig 1A)
To gain insight into whether the FUS-induced increases in glycogen synthase kinase-3b (GSK-3b) activity and reduced binding of VAPB to PTPIP51 were linked to the levels of cytosolic FUS, we investigated how these features were affected by a mutant FUS in which the C-terminal nuclear localization signal was deleted (FUSDC)

Summary

Introduction

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. 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. We show that FUS disrupts the VAPB–PTPIP51 interaction and ER–mitochondria associations. We demonstrate that the FUS-induced reductions to ER–mitochondria associations and are linked to activation of glycogen synthase kinase-3b (GSK-3b), a kinase already strongly associated with ALS/ FTD

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Results

Conclusion