Pirenperone relieves the symptoms of fragile X syndrome in Fmr1 knockout mice
Abstract Fragile X syndrome (FXS) is a neurodevelopmental disorder that is caused by the loss of Fragile X-linked mental retardation protein (FMRP), an RNA binding protein that can bind and recognize different RNA structures and regulate the target mRNAs’ translation involved in neuronal synaptic pl...
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Nature Portfolio
2022-12-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-25582-8 |
| _version_ | 1811203872379633664 |
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| author | Yujeong Kim Se Jin Jeon Edson Luck Gonzales Dongpil Shin Chilly Gay Remonde TaeJin Ahn Chan Young Shin |
| author_facet | Yujeong Kim Se Jin Jeon Edson Luck Gonzales Dongpil Shin Chilly Gay Remonde TaeJin Ahn Chan Young Shin |
| author_sort | Yujeong Kim |
| collection | DOAJ |
| description | Abstract Fragile X syndrome (FXS) is a neurodevelopmental disorder that is caused by the loss of Fragile X-linked mental retardation protein (FMRP), an RNA binding protein that can bind and recognize different RNA structures and regulate the target mRNAs’ translation involved in neuronal synaptic plasticity. Perturbations of this gene expression network have been related to abnormal behavioral symptoms such as hyperactivity, and impulsivity. Considering the roles of FMRP in the modulation of mRNA translation, we investigated the differentially expressed genes which might be targeted to revert to normal and ameliorate behavioral symptoms. Gene expression data was analyzed and used the connectivity map (CMap) to understand the changes in gene expression in FXS and predict the effective drug candidates. We analyzed the GSE7329 dataset that had 15 control and 8 FXS patients’ lymphoblastoid samples. Among 924 genes, 42 genes were selected as signatures for CMap analysis, and 24 associated drugs were found. Pirenperone was selected as a potential drug candidate for FXS for its possible antipsychotic effect. Treatment of pirenperone increased the expression level of Fmr1 gene. Moreover, pirenperone rescued the behavioral deficits in Fmr1 KO mice including hyperactivity, spatial memory, and impulsivity. These results suggest that pirenperone is a new drug candidate for FXS, which should be verified in future studies. |
| first_indexed | 2024-04-12T03:03:19Z |
| format | Article |
| id | doaj.art-edcf42ab03b441d7bf4c4a5217a9b232 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-12T03:03:19Z |
| publishDate | 2022-12-01 |
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| spelling | doaj.art-edcf42ab03b441d7bf4c4a5217a9b2322022-12-22T03:50:36ZengNature PortfolioScientific Reports2045-23222022-12-0112111110.1038/s41598-022-25582-8Pirenperone relieves the symptoms of fragile X syndrome in Fmr1 knockout miceYujeong Kim0Se Jin Jeon1Edson Luck Gonzales2Dongpil Shin3Chilly Gay Remonde4TaeJin Ahn5Chan Young Shin6Department of Pharmacology and Department of Advanced Translational Medicine, School of Medicine, Konkuk UniversityDepartment of Integrative Biotechnology, College of Science and Technology, Sahmyook UniversityDepartment of Pharmacology and Department of Advanced Translational Medicine, School of Medicine, Konkuk UniversityDepartment of Pharmacology and Department of Advanced Translational Medicine, School of Medicine, Konkuk UniversityDepartment of Pharmacology and Department of Advanced Translational Medicine, School of Medicine, Konkuk UniversityDepartment of Life Science, Handong Global UniversityDepartment of Pharmacology and Department of Advanced Translational Medicine, School of Medicine, Konkuk UniversityAbstract Fragile X syndrome (FXS) is a neurodevelopmental disorder that is caused by the loss of Fragile X-linked mental retardation protein (FMRP), an RNA binding protein that can bind and recognize different RNA structures and regulate the target mRNAs’ translation involved in neuronal synaptic plasticity. Perturbations of this gene expression network have been related to abnormal behavioral symptoms such as hyperactivity, and impulsivity. Considering the roles of FMRP in the modulation of mRNA translation, we investigated the differentially expressed genes which might be targeted to revert to normal and ameliorate behavioral symptoms. Gene expression data was analyzed and used the connectivity map (CMap) to understand the changes in gene expression in FXS and predict the effective drug candidates. We analyzed the GSE7329 dataset that had 15 control and 8 FXS patients’ lymphoblastoid samples. Among 924 genes, 42 genes were selected as signatures for CMap analysis, and 24 associated drugs were found. Pirenperone was selected as a potential drug candidate for FXS for its possible antipsychotic effect. Treatment of pirenperone increased the expression level of Fmr1 gene. Moreover, pirenperone rescued the behavioral deficits in Fmr1 KO mice including hyperactivity, spatial memory, and impulsivity. These results suggest that pirenperone is a new drug candidate for FXS, which should be verified in future studies.https://doi.org/10.1038/s41598-022-25582-8 |
| spellingShingle | Yujeong Kim Se Jin Jeon Edson Luck Gonzales Dongpil Shin Chilly Gay Remonde TaeJin Ahn Chan Young Shin Pirenperone relieves the symptoms of fragile X syndrome in Fmr1 knockout mice Scientific Reports |
| title | Pirenperone relieves the symptoms of fragile X syndrome in Fmr1 knockout mice |
| title_full | Pirenperone relieves the symptoms of fragile X syndrome in Fmr1 knockout mice |
| title_fullStr | Pirenperone relieves the symptoms of fragile X syndrome in Fmr1 knockout mice |
| title_full_unstemmed | Pirenperone relieves the symptoms of fragile X syndrome in Fmr1 knockout mice |
| title_short | Pirenperone relieves the symptoms of fragile X syndrome in Fmr1 knockout mice |
| title_sort | pirenperone relieves the symptoms of fragile x syndrome in fmr1 knockout mice |
| url | https://doi.org/10.1038/s41598-022-25582-8 |
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