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

Radu Stoica; Sébastien Paillusson; Patricia Gomez-Suaga; Jacqueline C. Mitchell; Dawn H W Lau; Emma H. Gray; Rosa M. Sancho; Gema Vizcay-Barrena; Kurt J. De Vos; Christopher Shaw; Diane P. Hanger; Wendy Noble; Christopher C J Miller

doi:10.15252/embr.201541726

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

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

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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.

Original language	English
Article number	e201541726
Pages (from-to)	1326-1342
Journal	EMBO Reports
Volume	17
Issue number	9
Early online date	14 Jul 2016
DOIs	https://doi.org/10.15252/embr.201541726
Publication status	Published - 1 Sept 2016

Keywords

Amyotrophic lateral sclerosis
Frontotemporal dementia
Glycogen synthase kinase-3β
Protein tyrosine phosphatase interacting protein 51
Vesicle-associated membrane protein-associated protein B

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10.15252/embr.201541726Licence: CC BY

ALS/FTD‐associated FUS_STOICA_Accepted13June2016_GOLD VoRFinal published version, 2.62 MBLicence: CC BY

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Stoica, R., Paillusson, S., Gomez-Suaga, P., Mitchell, J. C., Lau, D. H. W., Gray, E. H., Sancho, R. M., Vizcay-Barrena, G., De Vos, K. J., Shaw, C., Hanger, D. P., Noble, W., & Miller, C. C. J. (2016). ALS/FTD-associated FUS activates GSK-3β to disrupt the VAPB-PTPIP51 interaction and ER-mitochondria associations. EMBO Reports, 17(9), 1326-1342. [e201541726]. https://doi.org/10.15252/embr.201541726

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

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.",

keywords = "Amyotrophic lateral sclerosis, Frontotemporal dementia, Glycogen synthase kinase-3β, Protein tyrosine phosphatase interacting protein 51, Vesicle-associated membrane protein-associated protein B",

author = "Radu Stoica and S{\'e}bastien Paillusson and Patricia Gomez-Suaga and Mitchell, {Jacqueline C.} and Lau, {Dawn H W} and Gray, {Emma H.} and Sancho, {Rosa M.} and Gema Vizcay-Barrena and {De Vos}, {Kurt J.} and Christopher Shaw and Hanger, {Diane P.} and Wendy Noble and Miller, {Christopher C J}",

year = "2016",

month = sep,

day = "1",

doi = "10.15252/embr.201541726",

language = "English",

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journal = "EMBO Reports",

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Stoica, R , Paillusson, S , Gomez-Suaga, P , Mitchell, JC , Lau, DHW , Gray, EH , Sancho, RM , Vizcay-Barrena, G , De Vos, KJ , Shaw, C , Hanger, DP , Noble, W & Miller, CCJ 2016, 'ALS/FTD-associated FUS activates GSK-3β to disrupt the VAPB-PTPIP51 interaction and ER-mitochondria associations', EMBO Reports, vol. 17, no. 9, e201541726, pp. 1326-1342. https://doi.org/10.15252/embr.201541726

TY - JOUR

T1 - ALS/FTD-associated FUS activates GSK-3β to disrupt the VAPB-PTPIP51 interaction and ER-mitochondria associations

AU - Stoica, Radu

AU - Paillusson, Sébastien

AU - Gomez-Suaga, Patricia

AU - Mitchell, Jacqueline C.

AU - Lau, Dawn H W

AU - Gray, Emma H.

AU - Sancho, Rosa M.

AU - Vizcay-Barrena, Gema

AU - De Vos, Kurt J.

AU - Shaw, Christopher

AU - Hanger, Diane P.

AU - Noble, Wendy

AU - Miller, Christopher C J

PY - 2016/9/1

Y1 - 2016/9/1

N2 - 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.

AB - 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.

KW - Amyotrophic lateral sclerosis

KW - Frontotemporal dementia

KW - Glycogen synthase kinase-3β

KW - Protein tyrosine phosphatase interacting protein 51

KW - Vesicle-associated membrane protein-associated protein B

UR - http://www.scopus.com/inward/record.url?scp=84978431619&partnerID=8YFLogxK

U2 - 10.15252/embr.201541726

DO - 10.15252/embr.201541726

M3 - Article

SN - 1469-221X

VL - 17

SP - 1326

EP - 1342

JO - EMBO Reports

JF - EMBO Reports

IS - 9

M1 - e201541726

ER -

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

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