Lysosomal lipid alterations caused by glucocerebrosidase deficiency promote lysosomal dysfunction, chaperone-mediated-autophagy deficiency, and alpha-synuclein pathology

Mutations in the GBA gene that encodes the lysosomal enzyme β-glucocerebrosidase (GCase) are a major genetic risk factor for Parkinson's disease (PD). In this study, we generated a set of differentiated and stable human dopaminergic cell lines that express the two most prevalent GBA mutations a...

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Autores: Navarro-Romero, Alba, Fernandez-Gonzalez, Irene, Sánchez-Riera, Jordi, Montpeyó, Marta, Albert-Bayo, Merce, López-Royo, Tresa, Castillo-Sanchez, Pablo, Carnicer-Caceres, Clara, Arranz-Amo, Jose Antonio, Castillo-Ribelles, Laura, Pradas, Eddie, Casas, Josefina, Vila, Miquel, Martinez-Vicente, Marta
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/281529
Acceso en línea:http://hdl.handle.net/10261/281529
https://api.elsevier.com/content/abstract/scopus_id/85139971195
Access Level:acceso abierto
Palabra clave:Lysosomal lipid alterations
Parkinson's disease
GBA gene
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spelling Lysosomal lipid alterations caused by glucocerebrosidase deficiency promote lysosomal dysfunction, chaperone-mediated-autophagy deficiency, and alpha-synuclein pathologyNavarro-Romero, AlbaFernandez-Gonzalez, IreneSánchez-Riera, JordiMontpeyó, MartaAlbert-Bayo, MerceLópez-Royo, TresaCastillo-Sanchez, PabloCarnicer-Caceres, ClaraArranz-Amo, Jose AntonioCastillo-Ribelles, LauraPradas, EddieCasas, JosefinaVila, MiquelMartinez-Vicente, MartaLysosomal lipid alterationsParkinson's diseaseGBA geneMutations in the GBA gene that encodes the lysosomal enzyme β-glucocerebrosidase (GCase) are a major genetic risk factor for Parkinson's disease (PD). In this study, we generated a set of differentiated and stable human dopaminergic cell lines that express the two most prevalent GBA mutations as well as GBA knockout cell lines as a in vitro disease modeling system to study the relationship between mutant GBA and the abnormal accumulation of α-synuclein. We performed a deep analysis of the consequences triggered by the presence of mutant GBA protein and the loss of GCase activity in different cellular compartments, focusing primarily on the lysosomal compartment, and analyzed in detail the lysosomal activity, composition, and integrity. The loss of GCase activity generates extensive lysosomal dysfunction, promoting the loss of activity of other lysosomal enzymes, affecting lysosomal membrane stability, promoting intralysosomal pH changes, and favoring the intralysosomal accumulation of sphingolipids and cholesterol. These local events, occurring only at a subcellular level, lead to an impairment of autophagy pathways, particularly chaperone-mediated autophagy, the main α-synuclein degradative pathway. The findings of this study highlighted the role of lysosomal function and lipid metabolism in PD and allowed us to describe a molecular mechanism to understand how mutations in GBA can contribute to an abnormal accumulation of different α-synuclein neurotoxic species in PD pathology.The authors wish to thank Dr. Arango (VHIR) for the PX461 vector and all the Vila lab members for their support. This work was supported by the Fondo de Investigación Sanitaria-Instituto de Salud Carlos III (Spain)-FEDER (PI17/00496 and PI20/00728), the Michael J. Fox Foundation, the Silverstein Foundation (MJFF 16182), and the BBVA Foundation (NanoERT). M.M. was supported by an FPU doctoral fellowship (FPU18/05595) from MINECO (Spain); J.R. was supported by a PERIS fellowship (Generalitat de Catalunya); E.P. was supported by a VHIR doctoral fellowship (VHIR, Barcelona).Peer reviewedNature Publishing Group0000-0002-9241-10470000-0002-1352-989X0000-0001-7053-2625Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202220222022info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/281529https://api.elsevier.com/content/abstract/scopus_id/85139971195reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)InglésNPJ Parkinson's diseasehttps://doi.org/10.1038/s41531-022-00397-6Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2815292026-05-22T06:33:51Z
dc.title.none.fl_str_mv Lysosomal lipid alterations caused by glucocerebrosidase deficiency promote lysosomal dysfunction, chaperone-mediated-autophagy deficiency, and alpha-synuclein pathology
title Lysosomal lipid alterations caused by glucocerebrosidase deficiency promote lysosomal dysfunction, chaperone-mediated-autophagy deficiency, and alpha-synuclein pathology
spellingShingle Lysosomal lipid alterations caused by glucocerebrosidase deficiency promote lysosomal dysfunction, chaperone-mediated-autophagy deficiency, and alpha-synuclein pathology
Navarro-Romero, Alba
Lysosomal lipid alterations
Parkinson's disease
GBA gene
title_short Lysosomal lipid alterations caused by glucocerebrosidase deficiency promote lysosomal dysfunction, chaperone-mediated-autophagy deficiency, and alpha-synuclein pathology
title_full Lysosomal lipid alterations caused by glucocerebrosidase deficiency promote lysosomal dysfunction, chaperone-mediated-autophagy deficiency, and alpha-synuclein pathology
title_fullStr Lysosomal lipid alterations caused by glucocerebrosidase deficiency promote lysosomal dysfunction, chaperone-mediated-autophagy deficiency, and alpha-synuclein pathology
title_full_unstemmed Lysosomal lipid alterations caused by glucocerebrosidase deficiency promote lysosomal dysfunction, chaperone-mediated-autophagy deficiency, and alpha-synuclein pathology
title_sort Lysosomal lipid alterations caused by glucocerebrosidase deficiency promote lysosomal dysfunction, chaperone-mediated-autophagy deficiency, and alpha-synuclein pathology
dc.creator.none.fl_str_mv Navarro-Romero, Alba
Fernandez-Gonzalez, Irene
Sánchez-Riera, Jordi
Montpeyó, Marta
Albert-Bayo, Merce
López-Royo, Tresa
Castillo-Sanchez, Pablo
Carnicer-Caceres, Clara
Arranz-Amo, Jose Antonio
Castillo-Ribelles, Laura
Pradas, Eddie
Casas, Josefina
Vila, Miquel
Martinez-Vicente, Marta
author Navarro-Romero, Alba
author_facet Navarro-Romero, Alba
Fernandez-Gonzalez, Irene
Sánchez-Riera, Jordi
Montpeyó, Marta
Albert-Bayo, Merce
López-Royo, Tresa
Castillo-Sanchez, Pablo
Carnicer-Caceres, Clara
Arranz-Amo, Jose Antonio
Castillo-Ribelles, Laura
Pradas, Eddie
Casas, Josefina
Vila, Miquel
Martinez-Vicente, Marta
author_role author
author2 Fernandez-Gonzalez, Irene
Sánchez-Riera, Jordi
Montpeyó, Marta
Albert-Bayo, Merce
López-Royo, Tresa
Castillo-Sanchez, Pablo
Carnicer-Caceres, Clara
Arranz-Amo, Jose Antonio
Castillo-Ribelles, Laura
Pradas, Eddie
Casas, Josefina
Vila, Miquel
Martinez-Vicente, Marta
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv 0000-0002-9241-1047
0000-0002-1352-989X
0000-0001-7053-2625
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Lysosomal lipid alterations
Parkinson's disease
GBA gene
topic Lysosomal lipid alterations
Parkinson's disease
GBA gene
description Mutations in the GBA gene that encodes the lysosomal enzyme β-glucocerebrosidase (GCase) are a major genetic risk factor for Parkinson's disease (PD). In this study, we generated a set of differentiated and stable human dopaminergic cell lines that express the two most prevalent GBA mutations as well as GBA knockout cell lines as a in vitro disease modeling system to study the relationship between mutant GBA and the abnormal accumulation of α-synuclein. We performed a deep analysis of the consequences triggered by the presence of mutant GBA protein and the loss of GCase activity in different cellular compartments, focusing primarily on the lysosomal compartment, and analyzed in detail the lysosomal activity, composition, and integrity. The loss of GCase activity generates extensive lysosomal dysfunction, promoting the loss of activity of other lysosomal enzymes, affecting lysosomal membrane stability, promoting intralysosomal pH changes, and favoring the intralysosomal accumulation of sphingolipids and cholesterol. These local events, occurring only at a subcellular level, lead to an impairment of autophagy pathways, particularly chaperone-mediated autophagy, the main α-synuclein degradative pathway. The findings of this study highlighted the role of lysosomal function and lipid metabolism in PD and allowed us to describe a molecular mechanism to understand how mutations in GBA can contribute to an abnormal accumulation of different α-synuclein neurotoxic species in PD pathology.
publishDate 2022
dc.date.none.fl_str_mv 2022
2022
2022
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/10261/281529
https://api.elsevier.com/content/abstract/scopus_id/85139971195
url http://hdl.handle.net/10261/281529
https://api.elsevier.com/content/abstract/scopus_id/85139971195
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv NPJ Parkinson's disease
https://doi.org/10.1038/s41531-022-00397-6
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
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 15,811543

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