Inhibition of Prolyl Oligopeptidase Restores Prohibitin 2 Levels in Psychosis Models : Relationship to Cognitive Deficits in Schizophrenia
Vila, Èlia (Institut de Recerca Sant Joan de Déu)
Pinacho, Raquel (Institut de Recerca Sant Joan de Déu)
Prades, Roger (Iproteos S.L.)
Tarragó, Teresa (Iproteos S.L.)
Castro Fernánez, Elena (Institut de Salut Carlos III)
Munarriz-Cuezva, Eva (Institut de Salut Carlos III)
Meana, J. Javier (Institut de Salut Carlos III)
Eugui-Anta, Ania (Institut de Recerca Sant Joan de Déu)
Roldan Molina, Mònica (Hospital Sant Joan de Déu (Manresa))
Vera-Montecinos, América (Institut de Recerca Sant Joan de Déu)
Ramos, Belén (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)

Date:	2023
Abstract:	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.
Grants:	Instituto de Salud Carlos III PI18/00213
Rights:	Aquest 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.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Cognitive deficits ; Dizocilpine ; DLPFC ; PHB2 ; Postmortem ; Prolyl oligopeptidase ; Schizophrenia
Published in:	International journal of molecular sciences, Vol. 24 (march 2023) , ISSN 1422-0067

DOI: 10.3390/ijms24076016
PMID: 37046989

16 p, 1.2 MB

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