Therapeutic Targeting of the GSK3β-CUGBP1 Pathway in Myotonic Dystrophy
Myotonic Dystrophy type 1 (DM1) is a neuromuscular disease associated with toxic RNA containing expanded CUG repeats. The developing therapeutic approaches to DM1 target mutant RNA or correct early toxic events downstream of the mutant RNA. We have previously described the benefits of the correction...
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MDPI AG
2023-06-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/13/10650 |
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| author | Maggie Lutz Miranda Levanti Rebekah Karns Genevieve Gourdon Diana Lindquist Nikolai A. Timchenko Lubov Timchenko |
| author_facet | Maggie Lutz Miranda Levanti Rebekah Karns Genevieve Gourdon Diana Lindquist Nikolai A. Timchenko Lubov Timchenko |
| author_sort | Maggie Lutz |
| collection | DOAJ |
| description | Myotonic Dystrophy type 1 (DM1) is a neuromuscular disease associated with toxic RNA containing expanded CUG repeats. The developing therapeutic approaches to DM1 target mutant RNA or correct early toxic events downstream of the mutant RNA. We have previously described the benefits of the correction of the GSK3β-CUGBP1 pathway in DM1 mice (<i>HSA<sup>LR</sup></i> model) expressing 250 CUG repeats using the GSK3 inhibitor tideglusib (TG). Here, we show that TG treatments corrected the expression of ~17% of genes misregulated in DM1 mice, including genes involved in cell transport, development and differentiation. The expression of chloride channel 1 (<i>Clcn1</i>), the key trigger of myotonia in DM1, was also corrected by TG. We found that correction of the GSK3β-CUGBP1 pathway in mice expressing long CUG repeats (DMSXL model) is beneficial not only at the prenatal and postnatal stages, but also during adulthood. Using a mouse model with dysregulated CUGBP1, which mimics alterations in DM1, we showed that the dysregulated CUGBP1 contributes to the toxicity of expanded CUG repeats by changing gene expression and causing CNS abnormalities. These data show the critical role of the GSK3β-CUGBP1 pathway in DM1 muscle and in CNS pathologies, suggesting the benefits of GSK3 inhibitors in patients with different forms of DM1. |
| first_indexed | 2024-03-11T01:40:23Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T01:40:23Z |
| publishDate | 2023-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-c9cd2fbc31f041a88560c0eb06348b632023-11-18T16:41:26ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-06-0124131065010.3390/ijms241310650Therapeutic Targeting of the GSK3β-CUGBP1 Pathway in Myotonic DystrophyMaggie Lutz0Miranda Levanti1Rebekah Karns2Genevieve Gourdon3Diana Lindquist4Nikolai A. Timchenko5Lubov Timchenko6Division of Neurology, Cincinnati Children’s Hospital, Cincinnati, OH 45229, USADivision of Neurology, Cincinnati Children’s Hospital, Cincinnati, OH 45229, USADepartments of Gastroenterology, Hepatology & Nutrition, Cincinnati Children’s Hospital, Cincinnati, OH 45229, USASorbonne Université, Inserm, institut de Myologie, Centre de Recherche en Myologie, 75013 Paris, FranceImagine Research Center, Cincinnati Children’s Hospital, Cincinnati, OH 45229, USADepartment of Pediatrics, University of Cincinnati, Cincinnati, OH 45221, USADivision of Neurology, Cincinnati Children’s Hospital, Cincinnati, OH 45229, USAMyotonic Dystrophy type 1 (DM1) is a neuromuscular disease associated with toxic RNA containing expanded CUG repeats. The developing therapeutic approaches to DM1 target mutant RNA or correct early toxic events downstream of the mutant RNA. We have previously described the benefits of the correction of the GSK3β-CUGBP1 pathway in DM1 mice (<i>HSA<sup>LR</sup></i> model) expressing 250 CUG repeats using the GSK3 inhibitor tideglusib (TG). Here, we show that TG treatments corrected the expression of ~17% of genes misregulated in DM1 mice, including genes involved in cell transport, development and differentiation. The expression of chloride channel 1 (<i>Clcn1</i>), the key trigger of myotonia in DM1, was also corrected by TG. We found that correction of the GSK3β-CUGBP1 pathway in mice expressing long CUG repeats (DMSXL model) is beneficial not only at the prenatal and postnatal stages, but also during adulthood. Using a mouse model with dysregulated CUGBP1, which mimics alterations in DM1, we showed that the dysregulated CUGBP1 contributes to the toxicity of expanded CUG repeats by changing gene expression and causing CNS abnormalities. These data show the critical role of the GSK3β-CUGBP1 pathway in DM1 muscle and in CNS pathologies, suggesting the benefits of GSK3 inhibitors in patients with different forms of DM1.https://www.mdpi.com/1422-0067/24/13/10650Myotonic Dystrophy (DM1)congenital Myotonic Dystrophydevelopment of therapymyotoniabrain atrophyGSK3β |
| spellingShingle | Maggie Lutz Miranda Levanti Rebekah Karns Genevieve Gourdon Diana Lindquist Nikolai A. Timchenko Lubov Timchenko Therapeutic Targeting of the GSK3β-CUGBP1 Pathway in Myotonic Dystrophy International Journal of Molecular Sciences Myotonic Dystrophy (DM1) congenital Myotonic Dystrophy development of therapy myotonia brain atrophy GSK3β |
| title | Therapeutic Targeting of the GSK3β-CUGBP1 Pathway in Myotonic Dystrophy |
| title_full | Therapeutic Targeting of the GSK3β-CUGBP1 Pathway in Myotonic Dystrophy |
| title_fullStr | Therapeutic Targeting of the GSK3β-CUGBP1 Pathway in Myotonic Dystrophy |
| title_full_unstemmed | Therapeutic Targeting of the GSK3β-CUGBP1 Pathway in Myotonic Dystrophy |
| title_short | Therapeutic Targeting of the GSK3β-CUGBP1 Pathway in Myotonic Dystrophy |
| title_sort | therapeutic targeting of the gsk3β cugbp1 pathway in myotonic dystrophy |
| topic | Myotonic Dystrophy (DM1) congenital Myotonic Dystrophy development of therapy myotonia brain atrophy GSK3β |
| url | https://www.mdpi.com/1422-0067/24/13/10650 |
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