Rett syndrome: interferon-γ to the rescue?

Abstract

Rett syndrome is a severe neurodevelopmental disorder in girls, underpinned by mutations in the X-linked gene MECP2. In their recent work (Frasca et al, 2024), Frasca and colleagues identified a novel pathway involving interferon-gamma (IFNγ) that could pave the way to potential therapies.

Figure 1. MeCP2 structure, function and proposed mutant rescue.

Top: MeCP2 protein (486 aa) domain structure consisting of NTD N-terminal domain, MBD methyl binding domain, ID intervening domain, TRD transcription repression domain, NID NCoR interaction domain, CTD C-terminal domain, N nuclear localization signal. Middle: diagram of MeCP2 bound to methylated CpGs (black lollipops), recruiting transcription repressive complexes nuclear receptor corepressor 1 (NCoR)/silencing mediator for retinoid and thyroid hormone receptors (SMRT) and histone deacetylases (HDAC) to a gene neighborhood. Bottom: Mecp2 knockout (KO) neurons are defective but based on Frasca et al (2024) can be rescued by co-culture with neural progenitor cells (NPC, wild-type (WT) or KO) in vitro (trans-well co-culture experiments) or when NPC are transplanted into the brain (grey) of Mecp2 KO mice. Interferon γ (IFNγ) was shown to exert regenerative effects on Mecp2 KO neurons, attributed to an IFN pathway response to damage signals. WT neurons controls showed no effect.