Proteostasis regulators as potential rescuers of PMM2 activity

Phosphomannomutase 2 deficiency (PMM2-CDG) is the most common N-glycosylation disorder. To date there is no treatment. Following the identification of a number of destabilizing pathogenic variants, our group suggested PMM2-CDG to be a conformational disease. The aim of the present study was to evalu...

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Autores: Vilas, Alicia, Yuste-Checa, Patricia, Gallego, Diana, Desviat, Lourdes R., Ugarte, Magdalena, Pérez-Cerdá, Celia, Gámez, Alejandra, Pérez, Belén
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2020
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/342492
Acceso en línea:http://hdl.handle.net/10261/342492
Access Level:acceso abierto
Palabra clave:Congenital disorders of glycosylation
Molecular chaperones
Pharmacological chaperones
PMM2-CDG
Proteostasis regulators
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spelling Proteostasis regulators as potential rescuers of PMM2 activityVilas, AliciaYuste-Checa, PatriciaGallego, DianaDesviat, Lourdes R.Ugarte, MagdalenaPérez-Cerdá, CeliaGámez, AlejandraPérez, BelénCongenital disorders of glycosylationMolecular chaperonesPharmacological chaperonesPMM2-CDGProteostasis regulatorsPhosphomannomutase 2 deficiency (PMM2-CDG) is the most common N-glycosylation disorder. To date there is no treatment. Following the identification of a number of destabilizing pathogenic variants, our group suggested PMM2-CDG to be a conformational disease. The aim of the present study was to evaluate the possible use of proteostasis network regulators to increase the stability, and subsequently the enzymatic activity, of misfolded PMM2 mutant proteins. Patient-derived fibroblasts transduced with their own PMM2 folding or oligomerization variants were treated with different concentrations of the proteostasis regulators celastrol or MG132. Celastrol treatment led to a significant increase in mutant PMM2 protein concentration and activity, while MG132 had a small effect on protein concentration only. The increase in enzymatic activity with celastrol correlated with an increase in the transcriptional and proteome levels of the heat shock proteins Hsp90 and Hsp70. The use of specific Hsp70 or Hsp90 inhibitors showed the positive effect of celastrol on PMM2 stability and activity to occur through Hsp90-driven modulation of the proteostasis network. The synergistic effect of celastrol and a previously described pharmacological chaperone was also examined, and a mutation-dependent synergistic effect on PMM2 activity was noted. These results provide proof-of-concept regarding the potential treatment of PMM2-CDG by proteostasis regulators, either alone or in combination with pharmacological chaperones.This work was funded by the Fundación Isabel Gemio-Fundación La Caixa (LCF/PR/PR16/11110018), the Spanish Ministerio de Economía y Competitividad, and the Fondo Europeo de Desarrollo Regional (FEDER) PI16/00573, and the Regional Government of Madrid (CAM, B2017/BMD3721).Peer reviewedElsevierFundación Isabel GemioFundación la CaixaMinisterio de Economía y Competitividad (España)European CommissionComunidad de MadridConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202420242020info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/342492reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#B2017/BMD3721The underlying dataset has been published as supplementary material of the article in the publisher platform at http://dx.doi.org/10.1016/j.bbadis.2020.165777http://dx.doi.org/10.1016/j.bbadis.2020.165777Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3424922026-05-22T06:33:51Z
dc.title.none.fl_str_mv Proteostasis regulators as potential rescuers of PMM2 activity
title Proteostasis regulators as potential rescuers of PMM2 activity
spellingShingle Proteostasis regulators as potential rescuers of PMM2 activity
Vilas, Alicia
Congenital disorders of glycosylation
Molecular chaperones
Pharmacological chaperones
PMM2-CDG
Proteostasis regulators
title_short Proteostasis regulators as potential rescuers of PMM2 activity
title_full Proteostasis regulators as potential rescuers of PMM2 activity
title_fullStr Proteostasis regulators as potential rescuers of PMM2 activity
title_full_unstemmed Proteostasis regulators as potential rescuers of PMM2 activity
title_sort Proteostasis regulators as potential rescuers of PMM2 activity
dc.creator.none.fl_str_mv Vilas, Alicia
Yuste-Checa, Patricia
Gallego, Diana
Desviat, Lourdes R.
Ugarte, Magdalena
Pérez-Cerdá, Celia
Gámez, Alejandra
Pérez, Belén
author Vilas, Alicia
author_facet Vilas, Alicia
Yuste-Checa, Patricia
Gallego, Diana
Desviat, Lourdes R.
Ugarte, Magdalena
Pérez-Cerdá, Celia
Gámez, Alejandra
Pérez, Belén
author_role author
author2 Yuste-Checa, Patricia
Gallego, Diana
Desviat, Lourdes R.
Ugarte, Magdalena
Pérez-Cerdá, Celia
Gámez, Alejandra
Pérez, Belén
author2_role author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Fundación Isabel Gemio
Fundación la Caixa
Ministerio de Economía y Competitividad (España)
European Commission
Comunidad de Madrid
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Congenital disorders of glycosylation
Molecular chaperones
Pharmacological chaperones
PMM2-CDG
Proteostasis regulators
topic Congenital disorders of glycosylation
Molecular chaperones
Pharmacological chaperones
PMM2-CDG
Proteostasis regulators
description Phosphomannomutase 2 deficiency (PMM2-CDG) is the most common N-glycosylation disorder. To date there is no treatment. Following the identification of a number of destabilizing pathogenic variants, our group suggested PMM2-CDG to be a conformational disease. The aim of the present study was to evaluate the possible use of proteostasis network regulators to increase the stability, and subsequently the enzymatic activity, of misfolded PMM2 mutant proteins. Patient-derived fibroblasts transduced with their own PMM2 folding or oligomerization variants were treated with different concentrations of the proteostasis regulators celastrol or MG132. Celastrol treatment led to a significant increase in mutant PMM2 protein concentration and activity, while MG132 had a small effect on protein concentration only. The increase in enzymatic activity with celastrol correlated with an increase in the transcriptional and proteome levels of the heat shock proteins Hsp90 and Hsp70. The use of specific Hsp70 or Hsp90 inhibitors showed the positive effect of celastrol on PMM2 stability and activity to occur through Hsp90-driven modulation of the proteostasis network. The synergistic effect of celastrol and a previously described pharmacological chaperone was also examined, and a mutation-dependent synergistic effect on PMM2 activity was noted. These results provide proof-of-concept regarding the potential treatment of PMM2-CDG by proteostasis regulators, either alone or in combination with pharmacological chaperones.
publishDate 2020
dc.date.none.fl_str_mv 2020
2024
2024
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/10261/342492
url http://hdl.handle.net/10261/342492
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
B2017/BMD3721
The underlying dataset has been published as supplementary material of the article in the publisher platform at http://dx.doi.org/10.1016/j.bbadis.2020.165777
http://dx.doi.org/10.1016/j.bbadis.2020.165777
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
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)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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