Alexander disease mutations differentially sensitize glial fibrillary acidic protein (GFAP) to posttranslational modifications and network disruption by oxidants

The type III intermediate filament protein glial fibrillary acidic protein (GFAP) plays a key role in astrocyte and brain homeostasis. Mutations in GFAP can result in Alexander's disease (AxD), a severe neurodegenerative disease. Studies on AxD models indicate that oxidative stress may be an im...

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Autores: Goya-Iglesias, Nuria, Hägglund, Per, Martínez-Cenalmor, Paula, Nybo, Tina, Lorentzen, Lasse G, Pajares, María Ángeles, Davies, Michael J., Pérez-Sala, Dolores
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2026
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:dnet:digitalcsic_::9d49801a6cd728b1958346ef891cc6c5
Acceso en línea:http://hdl.handle.net/10261/425992
https://api.elsevier.com/content/abstract/scopus_id/105032479071
Access Level:acceso abierto
Palabra clave:Alexander disease (AxD)
Cysteine oxidation
Glial fibrillary acidic protein (GFAP)
Hydrogen peroxide
Posttranslational modifications (PTMs)
Protein oxidation
Proteomics
Vimentin
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dc.title.none.fl_str_mv Alexander disease mutations differentially sensitize glial fibrillary acidic protein (GFAP) to posttranslational modifications and network disruption by oxidants
title Alexander disease mutations differentially sensitize glial fibrillary acidic protein (GFAP) to posttranslational modifications and network disruption by oxidants
spellingShingle Alexander disease mutations differentially sensitize glial fibrillary acidic protein (GFAP) to posttranslational modifications and network disruption by oxidants
Goya-Iglesias, Nuria
Alexander disease (AxD)
Cysteine oxidation
Glial fibrillary acidic protein (GFAP)
Hydrogen peroxide
Posttranslational modifications (PTMs)
Protein oxidation
Proteomics
Vimentin
title_short Alexander disease mutations differentially sensitize glial fibrillary acidic protein (GFAP) to posttranslational modifications and network disruption by oxidants
title_full Alexander disease mutations differentially sensitize glial fibrillary acidic protein (GFAP) to posttranslational modifications and network disruption by oxidants
title_fullStr Alexander disease mutations differentially sensitize glial fibrillary acidic protein (GFAP) to posttranslational modifications and network disruption by oxidants
title_full_unstemmed Alexander disease mutations differentially sensitize glial fibrillary acidic protein (GFAP) to posttranslational modifications and network disruption by oxidants
title_sort Alexander disease mutations differentially sensitize glial fibrillary acidic protein (GFAP) to posttranslational modifications and network disruption by oxidants
dc.creator.none.fl_str_mv Goya-Iglesias, Nuria
Hägglund, Per
Martínez-Cenalmor, Paula
Nybo, Tina
Lorentzen, Lasse G
Pajares, María Ángeles
Davies, Michael J.
Pérez-Sala, Dolores
author Goya-Iglesias, Nuria
author_facet Goya-Iglesias, Nuria
Hägglund, Per
Martínez-Cenalmor, Paula
Nybo, Tina
Lorentzen, Lasse G
Pajares, María Ángeles
Davies, Michael J.
Pérez-Sala, Dolores
author_role author
author2 Hägglund, Per
Martínez-Cenalmor, Paula
Nybo, Tina
Lorentzen, Lasse G
Pajares, María Ángeles
Davies, Michael J.
Pérez-Sala, Dolores
author2_role author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Catalunya Caixa
Ministerio de Ciencia e Innovación (España)
Comunidad de Madrid
Novo Nordisk Foundation
University of Copenhagen
0000-0002-5196-6919 [Davies, Michael J.]
0000-0003-0600-665X [Pérez-Sala, Dolores]
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Alexander disease (AxD)
Cysteine oxidation
Glial fibrillary acidic protein (GFAP)
Hydrogen peroxide
Posttranslational modifications (PTMs)
Protein oxidation
Proteomics
Vimentin
topic Alexander disease (AxD)
Cysteine oxidation
Glial fibrillary acidic protein (GFAP)
Hydrogen peroxide
Posttranslational modifications (PTMs)
Protein oxidation
Proteomics
Vimentin
description The type III intermediate filament protein glial fibrillary acidic protein (GFAP) plays a key role in astrocyte and brain homeostasis. Mutations in GFAP can result in Alexander's disease (AxD), a severe neurodegenerative disease. Studies on AxD models indicate that oxidative stress may be an important pathogenic factor. Cellular expression of certain GFAP AxD mutants can provoke oxidative stress and contribute to a pathogenic cycle, as GFAP itself is an important oxidant target. To understand the molecular mechanisms involved, we have carried out a detailed LC-MS/MS characterization of posttranslational modifications formed on recombinant GFAP wild-type and AxD-relevant mutants (R79C, R239C and E373K) in response to in vitro treatment with hydrogen peroxide (H2O2), hypochlorous acid (HOCl) and peroxynitrous acid (ONOOH). These data indicate that cysteine residues are key targets. AxD mutants show increased susceptibility to modification, with sulfinic and sulfonic acids detected at both the wild-type cysteine (C294), and cysteine residues introduced by disease-related mutations. Mutation-selective variations in nitrations (from ONOOH) and chlorinations (from HOCl) were also detected. Formation of disulfide bonds, some of which involved mutation-introduced cysteine residues, results in GFAP oligomerization in vitro and in cells. Astrocytoma cells transfected with GFP-GFAP wild-type undergo morphologically-distinct remodeling in response to oxidants. In contrast, cells expressing the R239C mutation showed persistent or increased aggregates, particularly after H2O2 treatment. Together, these data show that AxD-associated GFAP mutations favor reversible and irreversible oxidative protein modifications, potentially contributing to impaired protein filament assembly and more severe responses to oxidative stress.
publishDate 2026
dc.date.none.fl_str_mv 2026
2026
2026
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/425992
https://api.elsevier.com/content/abstract/scopus_id/105032479071
url http://hdl.handle.net/10261/425992
https://api.elsevier.com/content/abstract/scopus_id/105032479071
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
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dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
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reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
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spelling Alexander disease mutations differentially sensitize glial fibrillary acidic protein (GFAP) to posttranslational modifications and network disruption by oxidantsGoya-Iglesias, NuriaHägglund, PerMartínez-Cenalmor, PaulaNybo, TinaLorentzen, Lasse GPajares, María ÁngelesDavies, Michael J.Pérez-Sala, DoloresAlexander disease (AxD)Cysteine oxidationGlial fibrillary acidic protein (GFAP)Hydrogen peroxidePosttranslational modifications (PTMs)Protein oxidationProteomicsVimentinThe type III intermediate filament protein glial fibrillary acidic protein (GFAP) plays a key role in astrocyte and brain homeostasis. Mutations in GFAP can result in Alexander's disease (AxD), a severe neurodegenerative disease. Studies on AxD models indicate that oxidative stress may be an important pathogenic factor. Cellular expression of certain GFAP AxD mutants can provoke oxidative stress and contribute to a pathogenic cycle, as GFAP itself is an important oxidant target. To understand the molecular mechanisms involved, we have carried out a detailed LC-MS/MS characterization of posttranslational modifications formed on recombinant GFAP wild-type and AxD-relevant mutants (R79C, R239C and E373K) in response to in vitro treatment with hydrogen peroxide (H2O2), hypochlorous acid (HOCl) and peroxynitrous acid (ONOOH). These data indicate that cysteine residues are key targets. AxD mutants show increased susceptibility to modification, with sulfinic and sulfonic acids detected at both the wild-type cysteine (C294), and cysteine residues introduced by disease-related mutations. Mutation-selective variations in nitrations (from ONOOH) and chlorinations (from HOCl) were also detected. Formation of disulfide bonds, some of which involved mutation-introduced cysteine residues, results in GFAP oligomerization in vitro and in cells. Astrocytoma cells transfected with GFP-GFAP wild-type undergo morphologically-distinct remodeling in response to oxidants. In contrast, cells expressing the R239C mutation showed persistent or increased aggregates, particularly after H2O2 treatment. Together, these data show that AxD-associated GFAP mutations favor reversible and irreversible oxidative protein modifications, potentially contributing to impaired protein filament assembly and more severe responses to oxidative stress.We are grateful to Dr. Elena Hernández-Gerez for preliminary experiments with astrocytoma cells, and to Dr. Eduardo Fuentes-Lemus for his contributions to the early stages of the LC-MS/MS analyses. The expert assistance from the personnel of the Flow Cytometry and Optical Microscopy facilities of the CIB Margarita Salas is gratefully acknowledged. This work was supported by Grant LCF/PR/HR21/52410002, “Astromad”, from Fundación “la Caixa” to M.J.D. and D.P.-S, and grant PID2021-126827OB-I00, funded by MCIN/AEI/10.13039/501100011033 and by “ERDF A way of making Europe” to D.P.-S. N.G.I. has been supported by fellowship (PIPF-2022/SAL-GL-25771) funded by Comunidad Autónoma de Madrid. M.J.D., P.M.H., T.N. and L.G.L. gratefully acknowledge support from the Novo Nordisk Foundation (grant NNF20SA0064214 to M.J.D) and the Novo Nordisk Foundation-University of Copenhagen BRIDGE scheme (to L.G.L.).Peer reviewedElsevierCatalunya CaixaMinisterio de Ciencia e Innovación (España)Comunidad de MadridNovo Nordisk FoundationUniversity of Copenhagen0000-0002-5196-6919 [Davies, Michael J.]0000-0003-0600-665X [Pérez-Sala, Dolores]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202620262026info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/425992https://api.elsevier.com/content/abstract/scopus_id/105032479071reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#LCF/PR/HR21/52410002PID2021-126827OB-I00MCIN/AEI/10.13039/501100011033PIPF-2022/SAL-GL-25771NNF20SA0064214https://doi.org/10.1016/j.redox.2026.104103Síinfo:eu-repo/semantics/openAccessoai:dnet:digitalcsic_::9d49801a6cd728b1958346ef891cc6c52026-05-22T06:33:51Z
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