Repurposing the NRF2 activator dimethyl fumarate as therapy against synucleinopathy in Parkinson's disease

Aims: This preclinical study was aimed at determining whether pharmacological targeting of transcription factor NRF2, a master controller of many homeostatic genes, might provide a disease-modifying therapy in the animal model of Parkinson's disease (PD) that best reproduces the main hallmark o...

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Authors: Lastres Becker, Isabel, García Yagüe, Ángel Juan, Scannevin, Robert H., Casarejos, María José, Kügler, Sebastian, Rábano, Alberto, Cuadrado Pastor, Antonio
Format: article
Publication Date:2016
Country:España
Institution:Universidad Autónoma de Madrid
Repository:Biblos-e Archivo. Repositorio Institucional de la UAM
Language:English
OAI Identifier:oai:repositorio.uam.es:10486/729020
Online Access:https://hdl.handle.net/10486/729020
https://dx.doi.org/10.1089/ars.2015.6549
Access Level:Open access
Keyword:NRF2
synucleinopathy
Parkinson disease
Medicina
Química
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spelling Repurposing the NRF2 activator dimethyl fumarate as therapy against synucleinopathy in Parkinson's diseaseLastres Becker, IsabelGarcía Yagüe, Ángel JuanScannevin, Robert H.Casarejos, María JoséKügler, SebastianRábano, AlbertoCuadrado Pastor, AntonioNRF2synucleinopathyParkinson diseaseMedicinaQuímicaAims: This preclinical study was aimed at determining whether pharmacological targeting of transcription factor NRF2, a master controller of many homeostatic genes, might provide a disease-modifying therapy in the animal model of Parkinson's disease (PD) that best reproduces the main hallmark of this pathology, that is, α-synucleinopathy, and associated events, including nigral dopaminergic cell death, oxidative stress, and neuroinflammation. Results: Pharmacological activation of NRF2 was achieved at the basal ganglia by repurposing dimethyl fumarate (DMF), a drug already in use for the treatment of multiple sclerosis. Daily oral gavage of DMF protected nigral dopaminergic neurons against α-SYN toxicity and decreased astrocytosis and microgliosis after 1, 3, and 8 weeks from stereotaxic delivery to the ventral midbrain of recombinant adeno-associated viral vector expressing human α-synuclein. This protective effect was not observed in Nrf2-knockout mice. In vitro studies indicated that this neuroprotective effect was correlated with altered regulation of autophagy markers SQTSM1/p62 and LC3 in MN9D, BV2, and IMA 2.1 and with a shift in microglial dynamics toward a less pro-inflammatory and a more wound-healing phenotype. In postmortem samples of PD patients, the cytoprotective proteins associated with NRF2 expression, NQO1 and p62, were partly sequestered in Lewy bodies, suggesting impaired neuroprotective capacity of the NRF2 signature. Innovation: These experiments provide a compelling rationale for targeting NRF2 with DMF as a therapeutic strategy to reinforce endogenous brain defense mechanisms against PD-associated synucleinopathy. Conclusion: DMF is ready for clinical validation in PDThis work was supported by grants from Biogen, SAF2013-143271-R and “Fundación Salud 2000.” ILB was recipient of a Ramón y Cajal contract (MICINN-RYC)Mary Ann LiebertDepartamento de BioquímicaFacultad de Medicina20162016-07-08research articlehttp://purl.org/coar/resource_type/c_2df8fbb1AMhttp://purl.org/coar/version/c_ab4af688f83e57aainfo:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10486/729020https://dx.doi.org/10.1089/ars.2015.654927009601reponame:Biblos-e Archivo. Repositorio Institucional de la UAMinstname:Universidad Autónoma de MadridInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:repositorio.uam.es:10486/7290202026-06-23T12:46:27Z
dc.title.none.fl_str_mv Repurposing the NRF2 activator dimethyl fumarate as therapy against synucleinopathy in Parkinson's disease
title Repurposing the NRF2 activator dimethyl fumarate as therapy against synucleinopathy in Parkinson's disease
spellingShingle Repurposing the NRF2 activator dimethyl fumarate as therapy against synucleinopathy in Parkinson's disease
Lastres Becker, Isabel
NRF2
synucleinopathy
Parkinson disease
Medicina
Química
title_short Repurposing the NRF2 activator dimethyl fumarate as therapy against synucleinopathy in Parkinson's disease
title_full Repurposing the NRF2 activator dimethyl fumarate as therapy against synucleinopathy in Parkinson's disease
title_fullStr Repurposing the NRF2 activator dimethyl fumarate as therapy against synucleinopathy in Parkinson's disease
title_full_unstemmed Repurposing the NRF2 activator dimethyl fumarate as therapy against synucleinopathy in Parkinson's disease
title_sort Repurposing the NRF2 activator dimethyl fumarate as therapy against synucleinopathy in Parkinson's disease
dc.creator.none.fl_str_mv Lastres Becker, Isabel
García Yagüe, Ángel Juan
Scannevin, Robert H.
Casarejos, María José
Kügler, Sebastian
Rábano, Alberto
Cuadrado Pastor, Antonio
author Lastres Becker, Isabel
author_facet Lastres Becker, Isabel
García Yagüe, Ángel Juan
Scannevin, Robert H.
Casarejos, María José
Kügler, Sebastian
Rábano, Alberto
Cuadrado Pastor, Antonio
author_role author
author2 García Yagüe, Ángel Juan
Scannevin, Robert H.
Casarejos, María José
Kügler, Sebastian
Rábano, Alberto
Cuadrado Pastor, Antonio
author2_role author
author
author
author
author
author
dc.contributor.none.fl_str_mv Departamento de Bioquímica
Facultad de Medicina
dc.subject.none.fl_str_mv NRF2
synucleinopathy
Parkinson disease
Medicina
Química
topic NRF2
synucleinopathy
Parkinson disease
Medicina
Química
description Aims: This preclinical study was aimed at determining whether pharmacological targeting of transcription factor NRF2, a master controller of many homeostatic genes, might provide a disease-modifying therapy in the animal model of Parkinson's disease (PD) that best reproduces the main hallmark of this pathology, that is, α-synucleinopathy, and associated events, including nigral dopaminergic cell death, oxidative stress, and neuroinflammation. Results: Pharmacological activation of NRF2 was achieved at the basal ganglia by repurposing dimethyl fumarate (DMF), a drug already in use for the treatment of multiple sclerosis. Daily oral gavage of DMF protected nigral dopaminergic neurons against α-SYN toxicity and decreased astrocytosis and microgliosis after 1, 3, and 8 weeks from stereotaxic delivery to the ventral midbrain of recombinant adeno-associated viral vector expressing human α-synuclein. This protective effect was not observed in Nrf2-knockout mice. In vitro studies indicated that this neuroprotective effect was correlated with altered regulation of autophagy markers SQTSM1/p62 and LC3 in MN9D, BV2, and IMA 2.1 and with a shift in microglial dynamics toward a less pro-inflammatory and a more wound-healing phenotype. In postmortem samples of PD patients, the cytoprotective proteins associated with NRF2 expression, NQO1 and p62, were partly sequestered in Lewy bodies, suggesting impaired neuroprotective capacity of the NRF2 signature. Innovation: These experiments provide a compelling rationale for targeting NRF2 with DMF as a therapeutic strategy to reinforce endogenous brain defense mechanisms against PD-associated synucleinopathy. Conclusion: DMF is ready for clinical validation in PD
publishDate 2016
dc.date.none.fl_str_mv 2016
2016-07-08
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
AM
http://purl.org/coar/version/c_ab4af688f83e57aa
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/10486/729020
https://dx.doi.org/10.1089/ars.2015.6549
27009601
url https://hdl.handle.net/10486/729020
https://dx.doi.org/10.1089/ars.2015.6549
identifier_str_mv 27009601
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Mary Ann Liebert
publisher.none.fl_str_mv Mary Ann Liebert
dc.source.none.fl_str_mv reponame:Biblos-e Archivo. Repositorio Institucional de la UAM
instname:Universidad Autónoma de Madrid
instname_str Universidad Autónoma de Madrid
reponame_str Biblos-e Archivo. Repositorio Institucional de la UAM
collection Biblos-e Archivo. Repositorio Institucional de la UAM
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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