Treatment with a GSK-3β/HDAC Dual Inhibitor Restores Neuronal Survival and Maturation in an In Vitro and In Vivo Model of CDKL5 Deficiency Disorder

International Journal of Molecular Sciences

Andrea Milelli¹  Giorgio Medici²  Manuela Loi²  Giuseppe Galvani²  Stefania Trazzi²  Claudia Fuchs²  Laura Gennaccaro²  Nicola Mottolese²  Elisabetta Ciani²  Marianna Tassinari²  RobertoRimondini Giorgini³ 

[1] Department for Life Quality Studies, University of Bologna, 47921 Rimini, Italy;Department of Biomedical and Neuromotor Sciences, University of Bologna, Piazza di Porta San Donato 2, 40126 Bologna, Italy;Department of Medical and Clinical Sciences, University of Bologna, 40126 Bologna, Italy;

关键词: CDKL5 deficiency disorder;    GSK-3β;    HDAC6;    dual inhibitor;    neuronal survival;    hippocampal defects;   

DOI  :  10.3390/ijms22115950

来源: DOAJ

【 摘 要 】

Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene cause a rare neurodevelopmental disorder characterized by early-onset seizures and severe cognitive, motor, and visual impairments. To date there are no therapies for CDKL5 deficiency disorder (CDD). In view of the severity of the neurological phenotype of CDD patients it is widely assumed that CDKL5 may influence the activity of a variety of cellular pathways, suggesting that an approach aimed at targeting multiple cellular pathways simultaneously might be more effective for CDD. Previous findings showed that a single-target therapy aimed at normalizing impaired GSK-3β or histone deacetylase (HDAC) activity improved neurodevelopmental and cognitive alterations in a mouse model of CDD. Here we tested the ability of a first-in-class GSK-3β/HDAC dual inhibitor, Compound 11 (C11), to rescue CDD-related phenotypes. We found that C11, through inhibition of GSK-3β and HDAC6 activity, not only restored maturation, but also significantly improved survival of both human CDKL5-deficient cells and hippocampal neurons from Cdkl5 KO mice. Importantly, in vivo treatment with C11 restored synapse development, neuronal survival, and microglia over-activation, and improved motor and cognitive abilities of Cdkl5 KO mice, suggesting that dual GSK-3β/HDAC6 inhibitor therapy may have a wider therapeutic benefit in CDD patients.

【 授权许可】

Unknown