A Genome-Wide Functional Screen Identifies Enhancer and Protective Genes for Amyloid Beta-Peptide Toxicity

Alzheimer’s disease (AD) is known to be caused by amyloid β-peptide (Aβ) misfolded into β-sheets, but this knowledge has not yet led to treatments to prevent AD. To identify novel molecular players in Aβ toxicity, we carried out a genome-wide screen in Saccharomyces cerevisiae, using a library of 51...

ver descrição completa

Detalhes bibliográficos
Autores: Picón Pagès, Pol, Bosch Morato, Mònica, Subirana, Laia, Rubio Moscardó, Francisca, Guivernau, Biuse, Fanlo Ucar, Hugo, Zeylan, Melisa E., Senyuz, Simge, Herrera Fernández, Víctor, Vicente, Rubén, Fernández Fernández, José M., García Ojalvo, Jordi, Gursoy, Attila, Keskin, Ozlem, Oliva, Baldomero, Posas, Francesc, Nadal Clanchet, Eulàlia de, Muñoz, Francisco J.
Tipo de documento: artigo
Estado:Versão publicada
Data de publicação:2023
País:España
Recursos:Universidad de Barcelona
Repositório:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/220563
Acesso em linha:https://hdl.handle.net/2445/220563
Access Level:Acceso aberto
Palavra-chave:Malaltia d'Alzheimer
Amiloides
Cribratge genètic
Alzheimer's disease
Amyloid
Genetic screening
id ES_e48df2ef7a1ffaf420e11d3de8a15d61
oai_identifier_str oai:diposit.ub.edu:2445/220563
network_acronym_str ES
network_name_str España
repository_id_str
spelling A Genome-Wide Functional Screen Identifies Enhancer and Protective Genes for Amyloid Beta-Peptide ToxicityPicón Pagès, PolBosch Morato, MònicaSubirana, LaiaRubio Moscardó, FranciscaGuivernau, BiuseFanlo Ucar, HugoZeylan, Melisa E.Senyuz, SimgeHerrera Fernández, VíctorVicente, RubénFernández Fernández, José M.García Ojalvo, Jordi Gursoy, AttilaKeskin, OzlemOliva, BaldomeroPosas, FrancescNadal Clanchet, Eulàlia deMuñoz, Francisco J.Malaltia d'AlzheimerAmiloidesCribratge genèticAlzheimer's diseaseAmyloidGenetic screeningAlzheimer’s disease (AD) is known to be caused by amyloid β-peptide (Aβ) misfolded into β-sheets, but this knowledge has not yet led to treatments to prevent AD. To identify novel molecular players in Aβ toxicity, we carried out a genome-wide screen in Saccharomyces cerevisiae, using a library of 5154 gene knock-out strains expressing Aβ1–42. We identified 81 mammalian orthologue genes that enhance Aβ1–42 toxicity, while 157 were protective. Next, we performed interactome and text-mining studies to increase the number of genes and to identify the main cellular functions affected by Aβ oligomers (oAβ). We found that the most affected cellular functions were calcium regulation, protein translation and mitochondrial activity. We focused on SURF4, a protein that regulates the store-operated calcium channel (SOCE). An in vitro analysis using human neuroblastoma cells showed that SURF4 silencing induced higher intracellular calcium levels, while its overexpression decreased calcium entry. Furthermore, SURF4 silencing produced a significant reduction in cell death when cells were challenged with oAβ1–42, whereas SURF4 overexpression induced Aβ1–42 cytotoxicity. In summary, we identified new enhancer and protective activities for Aβ toxicity and showed that SURF4 contributes to oAβ1–42 neurotoxicity by decreasing SOCE activity.MDPI2023info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/220563Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona))reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.3390/ijms24021278International Journal Of Molecular Sciences, 2023, vol. 24, num. 2https://doi.org/10.3390/ijms24021278cc-by (c) Picón Pagès, Pol et al., 2023http://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/2205632026-05-27T06:46:51Z
dc.title.none.fl_str_mv A Genome-Wide Functional Screen Identifies Enhancer and Protective Genes for Amyloid Beta-Peptide Toxicity
title A Genome-Wide Functional Screen Identifies Enhancer and Protective Genes for Amyloid Beta-Peptide Toxicity
spellingShingle A Genome-Wide Functional Screen Identifies Enhancer and Protective Genes for Amyloid Beta-Peptide Toxicity
Picón Pagès, Pol
Malaltia d'Alzheimer
Amiloides
Cribratge genètic
Alzheimer's disease
Amyloid
Genetic screening
title_short A Genome-Wide Functional Screen Identifies Enhancer and Protective Genes for Amyloid Beta-Peptide Toxicity
title_full A Genome-Wide Functional Screen Identifies Enhancer and Protective Genes for Amyloid Beta-Peptide Toxicity
title_fullStr A Genome-Wide Functional Screen Identifies Enhancer and Protective Genes for Amyloid Beta-Peptide Toxicity
title_full_unstemmed A Genome-Wide Functional Screen Identifies Enhancer and Protective Genes for Amyloid Beta-Peptide Toxicity
title_sort A Genome-Wide Functional Screen Identifies Enhancer and Protective Genes for Amyloid Beta-Peptide Toxicity
dc.creator.none.fl_str_mv Picón Pagès, Pol
Bosch Morato, Mònica
Subirana, Laia
Rubio Moscardó, Francisca
Guivernau, Biuse
Fanlo Ucar, Hugo
Zeylan, Melisa E.
Senyuz, Simge
Herrera Fernández, Víctor
Vicente, Rubén
Fernández Fernández, José M.
García Ojalvo, Jordi
Gursoy, Attila
Keskin, Ozlem
Oliva, Baldomero
Posas, Francesc
Nadal Clanchet, Eulàlia de
Muñoz, Francisco J.
author Picón Pagès, Pol
author_facet Picón Pagès, Pol
Bosch Morato, Mònica
Subirana, Laia
Rubio Moscardó, Francisca
Guivernau, Biuse
Fanlo Ucar, Hugo
Zeylan, Melisa E.
Senyuz, Simge
Herrera Fernández, Víctor
Vicente, Rubén
Fernández Fernández, José M.
García Ojalvo, Jordi
Gursoy, Attila
Keskin, Ozlem
Oliva, Baldomero
Posas, Francesc
Nadal Clanchet, Eulàlia de
Muñoz, Francisco J.
author_role author
author2 Bosch Morato, Mònica
Subirana, Laia
Rubio Moscardó, Francisca
Guivernau, Biuse
Fanlo Ucar, Hugo
Zeylan, Melisa E.
Senyuz, Simge
Herrera Fernández, Víctor
Vicente, Rubén
Fernández Fernández, José M.
García Ojalvo, Jordi
Gursoy, Attila
Keskin, Ozlem
Oliva, Baldomero
Posas, Francesc
Nadal Clanchet, Eulàlia de
Muñoz, Francisco J.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Malaltia d'Alzheimer
Amiloides
Cribratge genètic
Alzheimer's disease
Amyloid
Genetic screening
topic Malaltia d'Alzheimer
Amiloides
Cribratge genètic
Alzheimer's disease
Amyloid
Genetic screening
description Alzheimer’s disease (AD) is known to be caused by amyloid β-peptide (Aβ) misfolded into β-sheets, but this knowledge has not yet led to treatments to prevent AD. To identify novel molecular players in Aβ toxicity, we carried out a genome-wide screen in Saccharomyces cerevisiae, using a library of 5154 gene knock-out strains expressing Aβ1–42. We identified 81 mammalian orthologue genes that enhance Aβ1–42 toxicity, while 157 were protective. Next, we performed interactome and text-mining studies to increase the number of genes and to identify the main cellular functions affected by Aβ oligomers (oAβ). We found that the most affected cellular functions were calcium regulation, protein translation and mitochondrial activity. We focused on SURF4, a protein that regulates the store-operated calcium channel (SOCE). An in vitro analysis using human neuroblastoma cells showed that SURF4 silencing induced higher intracellular calcium levels, while its overexpression decreased calcium entry. Furthermore, SURF4 silencing produced a significant reduction in cell death when cells were challenged with oAβ1–42, whereas SURF4 overexpression induced Aβ1–42 cytotoxicity. In summary, we identified new enhancer and protective activities for Aβ toxicity and showed that SURF4 contributes to oAβ1–42 neurotoxicity by decreasing SOCE activity.
publishDate 2023
dc.date.none.fl_str_mv 2023
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://hdl.handle.net/2445/220563
url https://hdl.handle.net/2445/220563
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/10.3390/ijms24021278
International Journal Of Molecular Sciences, 2023, vol. 24, num. 2
https://doi.org/10.3390/ijms24021278
dc.rights.none.fl_str_mv cc-by (c) Picón Pagès, Pol et al., 2023
http://creativecommons.org/licenses/by/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Picón Pagès, Pol et al., 2023
http://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona))
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869422601086959616
score 15,81155

Registros relacionados