Inhibition of Prolyl Oligopeptidase Restores Prohibitin 2 Levels in Psychosis Models

Cognitive impairment represents one of the core features of schizophrenia. Prolyl Oligopeptidase (POP) inhibition is an emerging strategy for compensating cognitive deficits in hypoglutamatergic states such as schizophrenia, although little is known about how POP inhibitors exert their pharmacologic...

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Autores: Vila, Èlia|||0000-0003-2790-5400, Pinacho, Raquel|||0000-0001-6417-5983, Prades, Roger, Tarragó, Teresa, Castro Fernánez, Elena, Munarriz-Cuezva, Eva|||0000-0003-1943-3642, Meana, J. Javier|||0000-0002-7913-6714, Eugui-Anta, Ania, Roldan Molina, Mònica|||0000-0002-9530-6234, Vera Montecinos, América|||0000-0002-3468-0556, Ramos Josemaría, Belén|||0000-0002-4577-2106
Formato: artículo
Fecha de publicación:2023
País:España
Recursos:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:281677
Acesso em linha:https://ddd.uab.cat/record/281677
https://dx.doi.org/urn:doi:10.3390/ijms24076016
Access Level:acceso abierto
Palavra-chave:Cognitive deficits
Dizocilpine
DLPFC
PHB2
Postmortem
Prolyl oligopeptidase
Schizophrenia
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spelling Inhibition of Prolyl Oligopeptidase Restores Prohibitin 2 Levels in Psychosis ModelsRelationship to Cognitive Deficits in SchizophreniaVila, Èlia|||0000-0003-2790-5400Pinacho, Raquel|||0000-0001-6417-5983Prades, RogerTarragó, TeresaCastro Fernánez, ElenaMunarriz-Cuezva, Eva|||0000-0003-1943-3642Meana, J. Javier|||0000-0002-7913-6714Eugui-Anta, AniaRoldan Molina, Mònica|||0000-0002-9530-6234Vera Montecinos, América|||0000-0002-3468-0556Ramos Josemaría, Belén|||0000-0002-4577-2106Cognitive deficitsDizocilpineDLPFCPHB2PostmortemProlyl oligopeptidaseSchizophreniaCognitive impairment represents one of the core features of schizophrenia. Prolyl Oligopeptidase (POP) inhibition is an emerging strategy for compensating cognitive deficits in hypoglutamatergic states such as schizophrenia, although little is known about how POP inhibitors exert their pharmacological activity. The mitochondrial and nuclear protein Prohibitin 2 (PHB2) could be dysregulated in schizophrenia. However, altered PHB2 levels in schizophrenia linked to N-methyl-D-aspartate receptor (NMDAR) activity and cognitive deficits are still unknown. To shed light on this, we measured the PHB2 levels by immunoblot in a postmortem dorsolateral prefrontal cortex (DLPFC) of schizophrenia subjects, in the frontal pole of mice treated with the NMDAR antagonists phencyclidine and dizocilpine, and in rat cortical astrocytes and neurons treated with dizocilpine. Mice and cells were treated in combination with the POP inhibitor IPR19. The PHB2 levels were also analyzed by immunocytochemistry in rat neurons. The PHB2 levels increased in DLPFC in cases of chronic schizophrenia and were associated with cognitive impairments. NMDAR antagonists increased PHB2 levels in the frontal pole of mice and in rat astrocytes and neurons. High levels of PHB2 were found in the nucleus and cytoplasm of neurons upon NMDAR inhibition. IPR19 restored PHB2 levels in the acute NMDAR inhibition. These results show that IPR19 restores the upregulation of PHB2 in an acute NMDAR hypoactivity stage suggesting that the modulation of PHB2 could compensate NMDAR-dependent cognitive impairments in schizophrenia. 22023-01-0120232023-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/281677https://dx.doi.org/urn:doi:10.3390/ijms24076016reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengInstituto de Salud Carlos III https://doi.org/10.13039/501100004587 PI18/00213open accesshttp://purl.org/coar/access_right/c_abf2Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:2816772026-06-06T12:50:31Z
dc.title.none.fl_str_mv Inhibition of Prolyl Oligopeptidase Restores Prohibitin 2 Levels in Psychosis Models
Relationship to Cognitive Deficits in Schizophrenia
title Inhibition of Prolyl Oligopeptidase Restores Prohibitin 2 Levels in Psychosis Models
spellingShingle Inhibition of Prolyl Oligopeptidase Restores Prohibitin 2 Levels in Psychosis Models
Vila, Èlia|||0000-0003-2790-5400
Cognitive deficits
Dizocilpine
DLPFC
PHB2
Postmortem
Prolyl oligopeptidase
Schizophrenia
title_short Inhibition of Prolyl Oligopeptidase Restores Prohibitin 2 Levels in Psychosis Models
title_full Inhibition of Prolyl Oligopeptidase Restores Prohibitin 2 Levels in Psychosis Models
title_fullStr Inhibition of Prolyl Oligopeptidase Restores Prohibitin 2 Levels in Psychosis Models
title_full_unstemmed Inhibition of Prolyl Oligopeptidase Restores Prohibitin 2 Levels in Psychosis Models
title_sort Inhibition of Prolyl Oligopeptidase Restores Prohibitin 2 Levels in Psychosis Models
dc.creator.none.fl_str_mv Vila, Èlia|||0000-0003-2790-5400
Pinacho, Raquel|||0000-0001-6417-5983
Prades, Roger
Tarragó, Teresa
Castro Fernánez, Elena
Munarriz-Cuezva, Eva|||0000-0003-1943-3642
Meana, J. Javier|||0000-0002-7913-6714
Eugui-Anta, Ania
Roldan Molina, Mònica|||0000-0002-9530-6234
Vera Montecinos, América|||0000-0002-3468-0556
Ramos Josemaría, Belén|||0000-0002-4577-2106
author Vila, Èlia|||0000-0003-2790-5400
author_facet Vila, Èlia|||0000-0003-2790-5400
Pinacho, Raquel|||0000-0001-6417-5983
Prades, Roger
Tarragó, Teresa
Castro Fernánez, Elena
Munarriz-Cuezva, Eva|||0000-0003-1943-3642
Meana, J. Javier|||0000-0002-7913-6714
Eugui-Anta, Ania
Roldan Molina, Mònica|||0000-0002-9530-6234
Vera Montecinos, América|||0000-0002-3468-0556
Ramos Josemaría, Belén|||0000-0002-4577-2106
author_role author
author2 Pinacho, Raquel|||0000-0001-6417-5983
Prades, Roger
Tarragó, Teresa
Castro Fernánez, Elena
Munarriz-Cuezva, Eva|||0000-0003-1943-3642
Meana, J. Javier|||0000-0002-7913-6714
Eugui-Anta, Ania
Roldan Molina, Mònica|||0000-0002-9530-6234
Vera Montecinos, América|||0000-0002-3468-0556
Ramos Josemaría, Belén|||0000-0002-4577-2106
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Cognitive deficits
Dizocilpine
DLPFC
PHB2
Postmortem
Prolyl oligopeptidase
Schizophrenia
topic Cognitive deficits
Dizocilpine
DLPFC
PHB2
Postmortem
Prolyl oligopeptidase
Schizophrenia
description Cognitive impairment represents one of the core features of schizophrenia. Prolyl Oligopeptidase (POP) inhibition is an emerging strategy for compensating cognitive deficits in hypoglutamatergic states such as schizophrenia, although little is known about how POP inhibitors exert their pharmacological activity. The mitochondrial and nuclear protein Prohibitin 2 (PHB2) could be dysregulated in schizophrenia. However, altered PHB2 levels in schizophrenia linked to N-methyl-D-aspartate receptor (NMDAR) activity and cognitive deficits are still unknown. To shed light on this, we measured the PHB2 levels by immunoblot in a postmortem dorsolateral prefrontal cortex (DLPFC) of schizophrenia subjects, in the frontal pole of mice treated with the NMDAR antagonists phencyclidine and dizocilpine, and in rat cortical astrocytes and neurons treated with dizocilpine. Mice and cells were treated in combination with the POP inhibitor IPR19. The PHB2 levels were also analyzed by immunocytochemistry in rat neurons. The PHB2 levels increased in DLPFC in cases of chronic schizophrenia and were associated with cognitive impairments. NMDAR antagonists increased PHB2 levels in the frontal pole of mice and in rat astrocytes and neurons. High levels of PHB2 were found in the nucleus and cytoplasm of neurons upon NMDAR inhibition. IPR19 restored PHB2 levels in the acute NMDAR inhibition. These results show that IPR19 restores the upregulation of PHB2 in an acute NMDAR hypoactivity stage suggesting that the modulation of PHB2 could compensate NMDAR-dependent cognitive impairments in schizophrenia.
publishDate 2023
dc.date.none.fl_str_mv 2
2023-01-01
2023
2023-01-01
dc.type.none.fl_str_mv Article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://ddd.uab.cat/record/281677
https://dx.doi.org/urn:doi:10.3390/ijms24076016
url https://ddd.uab.cat/record/281677
https://dx.doi.org/urn:doi:10.3390/ijms24076016
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 PI18/00213
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
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
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Dipòsit Digital de Documents de la UAB
instname:Universitat Autònoma de Barcelona
instname_str Universitat Autònoma de Barcelona
reponame_str Dipòsit Digital de Documents de la UAB
collection Dipòsit Digital de Documents de la UAB
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repository.mail.fl_str_mv
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