2020/11/10 by Hyeong-Min Lee, M. Bram Kuijer, Nerea Ruiz Blanes +9 · 1 citation
Biochemistry, Genetics and Molecular Biology · #Genetics and Neurodevelopmental Disorders #Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities #Ubiquitin and proteasome pathways
paper · pdf · doi:10.1186/s11689-020-09332-3
openalex publication_date 2020/11/10 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01
BACKGROUND: Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the X-linked methyl-CpG binding protein 2 (MeCP2) gene. While MeCP2 mutations are lethal in most males, females survive birth but show severe neurological defects. Because X-chromosome inactivation (XCI) is a random process, approximately 50% of the cells silence the wild-type (WT) copy of the MeCP2 gene. Thus, reactivating the silent WT copy of MeCP2 could provide therapeutic intervention for RTT. METHODS: Toward this goal, we screened ~ 28,000 small-molecule compounds from several libraries using a MeCP2-luciferase reporter cell line and cortical neurons from a MeCP2-EGFP mouse model. We used gain/increase of luminescence or fluorescence as a readout of MeCP2 reactivation and tested the efficacy of these drugs under different drug regimens, conditions, and cellular contexts. RESULTS: We identified inhibitors of the JAK/STAT pathway as XCI-reactivating agents, both by in vitro and ex vivo assays. In particular, we show that AG-490, a Janus Kinase 2 (JAK2) kinase inhibitor, and Jaki, a pan JAK/STAT inhibitor, are capable of reactivating MeCP2 from the inactive X chromosome, in different cellular contexts. CONCLUSIONS: Our results suggest that inhibition of the JAK/STAT pathway is a new potential pathway to reinstate MeCP2 gene expression as an efficient RTT treatment.