Aberrant regulation of the GSK-3b/NRF2 axis unveils a novel therapy for adrenoleukodystrophy

The nuclear factor erythroid 2-like 2 (NRF2) is the master regulator of endogenous antioxidant responses. Oxidative damage is a shared and early-appearing feature in X-linked adrenoleukodystrophy (X-ALD) patients and the mouse model (Abcd1 null mouse). This rare neurometabolic disease is caused by t...

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Autores: Ranea-Robles, Pablo, Launay, Nathalie, Ruiz, Montserrat, Calingasan, Noel Ylagan, Dumont, Magali, Naudí i Farré, Alba, Portero Otín, Manuel, Pamplona Gras, Reinald, Ferrer, Isidre, Beal, M. Flint, Fourcade, Stéphane, Pujol, Aurora
Tipo de documento: artigo
Estado:Versão publicada
Data de publicação:2018
País:España
Recursos:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositório:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10459.1/64816
Acesso em linha:https://doi.org/10.15252/emmm.201708604
http://hdl.handle.net/10459.1/64816
Access Level:Acceso aberto
Palavra-chave:Adrenoleukodystrophy
Dimethyl fumarate
GSK-3
NRF2
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spelling Aberrant regulation of the GSK-3b/NRF2 axis unveils a novel therapy for adrenoleukodystrophyRanea-Robles, PabloLaunay, NathalieRuiz, MontserratCalingasan, Noel YlaganDumont, MagaliNaudí i Farré, AlbaPortero Otín, ManuelPamplona Gras, ReinaldFerrer, IsidreBeal, M. FlintFourcade, StéphanePujol, AuroraAdrenoleukodystrophyDimethyl fumarateGSK-3NRF2The nuclear factor erythroid 2-like 2 (NRF2) is the master regulator of endogenous antioxidant responses. Oxidative damage is a shared and early-appearing feature in X-linked adrenoleukodystrophy (X-ALD) patients and the mouse model (Abcd1 null mouse). This rare neurometabolic disease is caused by the loss of function of the peroxisomal transporter ABCD1, leading to an accumulation of very long-chain fatty acids and the induction of reactive oxygen species of mitochondrial origin. Here, we identify an impaired NRF2 response caused by aberrant activity of GSK-3b. We find that GSK-3b inhibitors can significantly reactivate the blunted NRF2 response in patients’ fibroblasts. In the mouse models (Abcd1 and Abcd1 /Abcd2 / mice), oral administration of dimethyl fumarate (DMF/BG12/Tecfidera), an NRF2 activator in use for multiple sclerosis, normalized (i) mitochondrial depletion, (ii) bioenergetic failure, (iii) oxidative damage, and (iv) inflammation, highlighting an intricate cross-talk governing energetic and redox homeostasis in XALD. Importantly, DMF halted axonal degeneration and locomotor disability suggesting that therapies activating NRF2 hold therapeutic potential for X-ALD and other axonopathies with impaired GSK- 3b/NRF2 axis.This study was supported by grants from the Spanish Institute for Health Carlos III and “Fondo Europeo de Desarrollo Regional (FEDER), Union Europea, una manera de hacer Europa” [PFIS FI12/00457] to P.R-R., [FIS PI14/ 01115, FIS PI17/00134] to M.P.O., [FIS PI13/00584, FIS PI14/00328] to R.P., [FIS PI11/01043, FIS PI14/00410, FIS PI17/00916] to A.P., [Miguel Servet program CP11/00080, CPII16/00016, FIS PI15/00857] to S.F.; the European Commission [FP7-241622] to A.P., the European Leukodystrophy Association [ELA2012-033C1] to A.P; the Autonomous Government of Catalonia [SGR 2017SGR696] to R.P. and [SGR 2014SGR1430; 2017SGR1206] to A.P.; and the Centre for Biomedical Research on Rare Diseases (CIBERER) to N.L. and M.R. Locomotor experiments were performed by the SEFALer unit F5 (CIBERER) led by A.P.Wiley Open Access201820182018info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://doi.org/10.15252/emmm.201708604http://hdl.handle.net/10459.1/64816http://hdl.handle.net/10459.1/64816reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a https://doi.org/10.15252/emmm.201708604EMBO Molecular Medicine, 2018, vol.10, e8604info:eu-repo/grantAgreement/EC/FP7/241622cc-by (c) Pablo Ranea-Robles et al., 2018info:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by/4.0/oai:recercat.cat:10459.1/648162026-05-29T05:05:01Z
dc.title.none.fl_str_mv Aberrant regulation of the GSK-3b/NRF2 axis unveils a novel therapy for adrenoleukodystrophy
title Aberrant regulation of the GSK-3b/NRF2 axis unveils a novel therapy for adrenoleukodystrophy
spellingShingle Aberrant regulation of the GSK-3b/NRF2 axis unveils a novel therapy for adrenoleukodystrophy
Ranea-Robles, Pablo
Adrenoleukodystrophy
Dimethyl fumarate
GSK-3
NRF2
title_short Aberrant regulation of the GSK-3b/NRF2 axis unveils a novel therapy for adrenoleukodystrophy
title_full Aberrant regulation of the GSK-3b/NRF2 axis unveils a novel therapy for adrenoleukodystrophy
title_fullStr Aberrant regulation of the GSK-3b/NRF2 axis unveils a novel therapy for adrenoleukodystrophy
title_full_unstemmed Aberrant regulation of the GSK-3b/NRF2 axis unveils a novel therapy for adrenoleukodystrophy
title_sort Aberrant regulation of the GSK-3b/NRF2 axis unveils a novel therapy for adrenoleukodystrophy
dc.creator.none.fl_str_mv Ranea-Robles, Pablo
Launay, Nathalie
Ruiz, Montserrat
Calingasan, Noel Ylagan
Dumont, Magali
Naudí i Farré, Alba
Portero Otín, Manuel
Pamplona Gras, Reinald
Ferrer, Isidre
Beal, M. Flint
Fourcade, Stéphane
Pujol, Aurora
author Ranea-Robles, Pablo
author_facet Ranea-Robles, Pablo
Launay, Nathalie
Ruiz, Montserrat
Calingasan, Noel Ylagan
Dumont, Magali
Naudí i Farré, Alba
Portero Otín, Manuel
Pamplona Gras, Reinald
Ferrer, Isidre
Beal, M. Flint
Fourcade, Stéphane
Pujol, Aurora
author_role author
author2 Launay, Nathalie
Ruiz, Montserrat
Calingasan, Noel Ylagan
Dumont, Magali
Naudí i Farré, Alba
Portero Otín, Manuel
Pamplona Gras, Reinald
Ferrer, Isidre
Beal, M. Flint
Fourcade, Stéphane
Pujol, Aurora
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Adrenoleukodystrophy
Dimethyl fumarate
GSK-3
NRF2
topic Adrenoleukodystrophy
Dimethyl fumarate
GSK-3
NRF2
description The nuclear factor erythroid 2-like 2 (NRF2) is the master regulator of endogenous antioxidant responses. Oxidative damage is a shared and early-appearing feature in X-linked adrenoleukodystrophy (X-ALD) patients and the mouse model (Abcd1 null mouse). This rare neurometabolic disease is caused by the loss of function of the peroxisomal transporter ABCD1, leading to an accumulation of very long-chain fatty acids and the induction of reactive oxygen species of mitochondrial origin. Here, we identify an impaired NRF2 response caused by aberrant activity of GSK-3b. We find that GSK-3b inhibitors can significantly reactivate the blunted NRF2 response in patients’ fibroblasts. In the mouse models (Abcd1 and Abcd1 /Abcd2 / mice), oral administration of dimethyl fumarate (DMF/BG12/Tecfidera), an NRF2 activator in use for multiple sclerosis, normalized (i) mitochondrial depletion, (ii) bioenergetic failure, (iii) oxidative damage, and (iv) inflammation, highlighting an intricate cross-talk governing energetic and redox homeostasis in XALD. Importantly, DMF halted axonal degeneration and locomotor disability suggesting that therapies activating NRF2 hold therapeutic potential for X-ALD and other axonopathies with impaired GSK- 3b/NRF2 axis.
publishDate 2018
dc.date.none.fl_str_mv 2018
2018
2018
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://doi.org/10.15252/emmm.201708604
http://hdl.handle.net/10459.1/64816
http://hdl.handle.net/10459.1/64816
url https://doi.org/10.15252/emmm.201708604
http://hdl.handle.net/10459.1/64816
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a https://doi.org/10.15252/emmm.201708604
EMBO Molecular Medicine, 2018, vol.10, e8604
info:eu-repo/grantAgreement/EC/FP7/241622
dc.rights.none.fl_str_mv cc-by (c) Pablo Ranea-Robles et al., 2018
info:eu-repo/semantics/openAccess
http://creativecommons.org/licenses/by/4.0/
rights_invalid_str_mv cc-by (c) Pablo Ranea-Robles et al., 2018
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Wiley Open Access
publisher.none.fl_str_mv Wiley Open Access
dc.source.none.fl_str_mv reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869411601463902208
score 15,812455

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