Therapeutic Targeting of the GSK3β-CUGBP1 Pathway in Myotonic Dystrophy - Sorbonne Université Access content directly
Journal Articles International Journal of Molecular Sciences Year : 2023

Therapeutic Targeting of the GSK3β-CUGBP1 Pathway in Myotonic Dystrophy

Maggie Lutz
Miranda Levanti
  • Function : Author
  • PersonId : 1299810
Rebekah Karns
  • Function : Author
  • PersonId : 1299811
Diana Lindquist
  • Function : Author
  • PersonId : 1299812
Nikolai A Timchenko
  • Function : Author
  • PersonId : 1299813
Lubov Timchenko
  • Function : Author
  • PersonId : 1119114

Abstract

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 (HSALR 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 (Clcn1), 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.
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Dates and versions

hal-04259888 , version 1 (26-10-2023)

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Maggie Lutz, Miranda Levanti, Rebekah Karns, Genevieve Gourdon, Diana Lindquist, et al.. Therapeutic Targeting of the GSK3β-CUGBP1 Pathway in Myotonic Dystrophy. International Journal of Molecular Sciences, 2023, 24 (13), pp.10650. ⟨10.3390/ijms241310650⟩. ⟨hal-04259888⟩
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