Genomic and Reverse Translational Analysis Discloses a Role for Small GTPase RhoA Signaling in the Pathogenesis of Schizophrenia: Rho-Kinase as a Novel Drug Target
Schizophrenia is one of the most serious psychiatric disorders and is characterized by reductions in both brain volume and spine density in the frontal cortex. RhoA belongs to the RAS homolog (Rho) family and plays critical roles in neuronal development and structural plasticity via Rho-kinase. RhoA...
| Main Authors: | , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-10-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/24/21/15623 |
| _version_ | 1797631848013103104 |
|---|---|
| author | Rinako Tanaka Kiyofumi Yamada |
| author_facet | Rinako Tanaka Kiyofumi Yamada |
| author_sort | Rinako Tanaka |
| collection | DOAJ |
| description | Schizophrenia is one of the most serious psychiatric disorders and is characterized by reductions in both brain volume and spine density in the frontal cortex. RhoA belongs to the RAS homolog (Rho) family and plays critical roles in neuronal development and structural plasticity via Rho-kinase. RhoA activity is regulated by GTPase-activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs). Several variants in GAPs and GEFs associated with RhoA have been reported to be significantly associated with schizophrenia. Moreover, several mouse models carrying schizophrenia-associated gene variants involved in RhoA/Rho-kinase signaling have been developed. In this review, we summarize clinical evidence showing that variants in genes regulating RhoA activity are associated with schizophrenia. In the last half of the review, we discuss preclinical evidence indicating that RhoA/Rho-kinase is a potential therapeutic target of schizophrenia. In particular, Rho-kinase inhibitors exhibit anti-psychotic-like effects not only in <i>Arhgap10</i> S490P/NHEJ mice, but also in pharmacologic models of schizophrenia (methamphetamine- and MK-801-treated mice). Accordingly, we propose that Rho-kinase inhibitors may have antipsychotic effects and reduce cognitive deficits in schizophrenia despite the presence or absence of genetic variants in small GTPase signaling pathways. |
| first_indexed | 2024-03-11T11:28:31Z |
| format | Article |
| id | doaj.art-32df39538f814d4daf79cc18d238277d |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T11:28:31Z |
| publishDate | 2023-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-32df39538f814d4daf79cc18d238277d2023-11-10T15:04:40ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-10-0124211562310.3390/ijms242115623Genomic and Reverse Translational Analysis Discloses a Role for Small GTPase RhoA Signaling in the Pathogenesis of Schizophrenia: Rho-Kinase as a Novel Drug TargetRinako Tanaka0Kiyofumi Yamada1Department of Neuropsychopharmacology and Hospital Pharmacy, Graduate School of Medicine, Nagoya University, Nagoya 466-8560, JapanDepartment of Neuropsychopharmacology and Hospital Pharmacy, Graduate School of Medicine, Nagoya University, Nagoya 466-8560, JapanSchizophrenia is one of the most serious psychiatric disorders and is characterized by reductions in both brain volume and spine density in the frontal cortex. RhoA belongs to the RAS homolog (Rho) family and plays critical roles in neuronal development and structural plasticity via Rho-kinase. RhoA activity is regulated by GTPase-activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs). Several variants in GAPs and GEFs associated with RhoA have been reported to be significantly associated with schizophrenia. Moreover, several mouse models carrying schizophrenia-associated gene variants involved in RhoA/Rho-kinase signaling have been developed. In this review, we summarize clinical evidence showing that variants in genes regulating RhoA activity are associated with schizophrenia. In the last half of the review, we discuss preclinical evidence indicating that RhoA/Rho-kinase is a potential therapeutic target of schizophrenia. In particular, Rho-kinase inhibitors exhibit anti-psychotic-like effects not only in <i>Arhgap10</i> S490P/NHEJ mice, but also in pharmacologic models of schizophrenia (methamphetamine- and MK-801-treated mice). Accordingly, we propose that Rho-kinase inhibitors may have antipsychotic effects and reduce cognitive deficits in schizophrenia despite the presence or absence of genetic variants in small GTPase signaling pathways.https://www.mdpi.com/1422-0067/24/21/15623copy number variantsCNVssingle-nucleotide polymorphismsSNPsfasudilKalirin |
| spellingShingle | Rinako Tanaka Kiyofumi Yamada Genomic and Reverse Translational Analysis Discloses a Role for Small GTPase RhoA Signaling in the Pathogenesis of Schizophrenia: Rho-Kinase as a Novel Drug Target International Journal of Molecular Sciences copy number variants CNVs single-nucleotide polymorphisms SNPs fasudil Kalirin |
| title | Genomic and Reverse Translational Analysis Discloses a Role for Small GTPase RhoA Signaling in the Pathogenesis of Schizophrenia: Rho-Kinase as a Novel Drug Target |
| title_full | Genomic and Reverse Translational Analysis Discloses a Role for Small GTPase RhoA Signaling in the Pathogenesis of Schizophrenia: Rho-Kinase as a Novel Drug Target |
| title_fullStr | Genomic and Reverse Translational Analysis Discloses a Role for Small GTPase RhoA Signaling in the Pathogenesis of Schizophrenia: Rho-Kinase as a Novel Drug Target |
| title_full_unstemmed | Genomic and Reverse Translational Analysis Discloses a Role for Small GTPase RhoA Signaling in the Pathogenesis of Schizophrenia: Rho-Kinase as a Novel Drug Target |
| title_short | Genomic and Reverse Translational Analysis Discloses a Role for Small GTPase RhoA Signaling in the Pathogenesis of Schizophrenia: Rho-Kinase as a Novel Drug Target |
| title_sort | genomic and reverse translational analysis discloses a role for small gtpase rhoa signaling in the pathogenesis of schizophrenia rho kinase as a novel drug target |
| topic | copy number variants CNVs single-nucleotide polymorphisms SNPs fasudil Kalirin |
| url | https://www.mdpi.com/1422-0067/24/21/15623 |
| work_keys_str_mv | AT rinakotanaka genomicandreversetranslationalanalysisdisclosesaroleforsmallgtpaserhoasignalinginthepathogenesisofschizophreniarhokinaseasanoveldrugtarget AT kiyofumiyamada genomicandreversetranslationalanalysisdisclosesaroleforsmallgtpaserhoasignalinginthepathogenesisofschizophreniarhokinaseasanoveldrugtarget |