Ribosomal Protein S6 Hypofunction in Postmortem Human Brain Links mTORC1-Dependent Signaling and Schizophrenia
The mechanistic target of rapamycin (also known as mammalian target of rapamycin) (mTOR)-dependent signaling pathway plays an important role in protein synthesis, cell growth, and proliferation, and has been linked to the development of the central nervous system. Recent studies suggest that mTOR si...
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| Format: | Article |
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Frontiers Media S.A.
2020-03-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fphar.2020.00344/full |
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| author | Inés Ibarra-Lecue Rebeca Diez-Alarcia Rebeca Diez-Alarcia Benito Morentin Benito Morentin J. Javier Meana J. Javier Meana Luis F. Callado Luis F. Callado Leyre Urigüen Leyre Urigüen |
| author_facet | Inés Ibarra-Lecue Rebeca Diez-Alarcia Rebeca Diez-Alarcia Benito Morentin Benito Morentin J. Javier Meana J. Javier Meana Luis F. Callado Luis F. Callado Leyre Urigüen Leyre Urigüen |
| author_sort | Inés Ibarra-Lecue |
| collection | DOAJ |
| description | The mechanistic target of rapamycin (also known as mammalian target of rapamycin) (mTOR)-dependent signaling pathway plays an important role in protein synthesis, cell growth, and proliferation, and has been linked to the development of the central nervous system. Recent studies suggest that mTOR signaling pathway dysfunction could be involved in the etiopathogenesis of schizophrenia. The main goal of this study was to evaluate the status of mTOR signaling pathway in postmortem prefrontal cortex (PFC) samples of subjects with schizophrenia. For this purpose, we quantified the protein expression and phosphorylation status of the mTOR downstream effector ribosomal protein S6 as well as other pathway interactors such as Akt and GSK3β. Furthermore, we quantified the status of these proteins in the brain cortex of rats chronically treated with the antipsychotics haloperidol, clozapine, or risperidone. We found a striking decrease in the expression of total S6 and in its active phosphorylated form phospho-S6 (Ser235/236) in the brain of subjects with schizophrenia compared to matched controls. The chronic treatment with the antipsychotics haloperidol and clozapine affected both the expression of GSK3β and the activation of Akt [phospho-Akt (Ser473)] in rat brain cortex, while no changes were observed in S6 and phospho-S6 (Ser235/236) protein expression with any antipsychotic treatment. These findings provide further evidence for the involvement of the mTOR-dependent signaling pathway in schizophrenia and suggest that a hypofunctional S6 may have a role in the etiopathogenesis of this disorder. |
| first_indexed | 2024-04-13T03:54:50Z |
| format | Article |
| id | doaj.art-b1b5ae7dfa0d44109ae0b30e6289550f |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-13T03:54:50Z |
| publishDate | 2020-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-b1b5ae7dfa0d44109ae0b30e6289550f2022-12-22T03:03:41ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122020-03-011110.3389/fphar.2020.00344525773Ribosomal Protein S6 Hypofunction in Postmortem Human Brain Links mTORC1-Dependent Signaling and SchizophreniaInés Ibarra-Lecue0Rebeca Diez-Alarcia1Rebeca Diez-Alarcia2Benito Morentin3Benito Morentin4J. Javier Meana5J. Javier Meana6Luis F. Callado7Luis F. Callado8Leyre Urigüen9Leyre Urigüen10Department of Pharmacology, University of the Basque Country UPV/EHU and Centro de Investigación Biomédica en Red de Salud Mental CIBERSAM, Leioa, SpainDepartment of Pharmacology, University of the Basque Country UPV/EHU and Centro de Investigación Biomédica en Red de Salud Mental CIBERSAM, Leioa, SpainBiocruces Bizkaia Health Research Institute, Barakaldo, SpainBiocruces Bizkaia Health Research Institute, Barakaldo, SpainSection of Forensic Pathology, Basque Institute of Legal Medicine, Bilbao, SpainDepartment of Pharmacology, University of the Basque Country UPV/EHU and Centro de Investigación Biomédica en Red de Salud Mental CIBERSAM, Leioa, SpainBiocruces Bizkaia Health Research Institute, Barakaldo, SpainDepartment of Pharmacology, University of the Basque Country UPV/EHU and Centro de Investigación Biomédica en Red de Salud Mental CIBERSAM, Leioa, SpainBiocruces Bizkaia Health Research Institute, Barakaldo, SpainDepartment of Pharmacology, University of the Basque Country UPV/EHU and Centro de Investigación Biomédica en Red de Salud Mental CIBERSAM, Leioa, SpainBiocruces Bizkaia Health Research Institute, Barakaldo, SpainThe mechanistic target of rapamycin (also known as mammalian target of rapamycin) (mTOR)-dependent signaling pathway plays an important role in protein synthesis, cell growth, and proliferation, and has been linked to the development of the central nervous system. Recent studies suggest that mTOR signaling pathway dysfunction could be involved in the etiopathogenesis of schizophrenia. The main goal of this study was to evaluate the status of mTOR signaling pathway in postmortem prefrontal cortex (PFC) samples of subjects with schizophrenia. For this purpose, we quantified the protein expression and phosphorylation status of the mTOR downstream effector ribosomal protein S6 as well as other pathway interactors such as Akt and GSK3β. Furthermore, we quantified the status of these proteins in the brain cortex of rats chronically treated with the antipsychotics haloperidol, clozapine, or risperidone. We found a striking decrease in the expression of total S6 and in its active phosphorylated form phospho-S6 (Ser235/236) in the brain of subjects with schizophrenia compared to matched controls. The chronic treatment with the antipsychotics haloperidol and clozapine affected both the expression of GSK3β and the activation of Akt [phospho-Akt (Ser473)] in rat brain cortex, while no changes were observed in S6 and phospho-S6 (Ser235/236) protein expression with any antipsychotic treatment. These findings provide further evidence for the involvement of the mTOR-dependent signaling pathway in schizophrenia and suggest that a hypofunctional S6 may have a role in the etiopathogenesis of this disorder.https://www.frontiersin.org/article/10.3389/fphar.2020.00344/fullribosomal protein S6schizophreniamTORC1postmortem tissueantipsychotics |
| spellingShingle | Inés Ibarra-Lecue Rebeca Diez-Alarcia Rebeca Diez-Alarcia Benito Morentin Benito Morentin J. Javier Meana J. Javier Meana Luis F. Callado Luis F. Callado Leyre Urigüen Leyre Urigüen Ribosomal Protein S6 Hypofunction in Postmortem Human Brain Links mTORC1-Dependent Signaling and Schizophrenia Frontiers in Pharmacology ribosomal protein S6 schizophrenia mTORC1 postmortem tissue antipsychotics |
| title | Ribosomal Protein S6 Hypofunction in Postmortem Human Brain Links mTORC1-Dependent Signaling and Schizophrenia |
| title_full | Ribosomal Protein S6 Hypofunction in Postmortem Human Brain Links mTORC1-Dependent Signaling and Schizophrenia |
| title_fullStr | Ribosomal Protein S6 Hypofunction in Postmortem Human Brain Links mTORC1-Dependent Signaling and Schizophrenia |
| title_full_unstemmed | Ribosomal Protein S6 Hypofunction in Postmortem Human Brain Links mTORC1-Dependent Signaling and Schizophrenia |
| title_short | Ribosomal Protein S6 Hypofunction in Postmortem Human Brain Links mTORC1-Dependent Signaling and Schizophrenia |
| title_sort | ribosomal protein s6 hypofunction in postmortem human brain links mtorc1 dependent signaling and schizophrenia |
| topic | ribosomal protein S6 schizophrenia mTORC1 postmortem tissue antipsychotics |
| url | https://www.frontiersin.org/article/10.3389/fphar.2020.00344/full |
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