Expanding the MECP2 network using comparative genomics reveals potential therapeutic targets for Rett syndrome.

Area of Science:

• Genomics
• Neuroscience
• Drug Discovery

Background:

• Rett syndrome (RTT) is caused by inactivating mutations in the Methyl-CpG Binding Protein 2 (MECP2) gene.
• Currently, no effective treatments exist for RTT, despite significant research into MECP2 function.

Purpose of the Study:

• To utilize an evolutionary genomics approach to build an unbiased MECP2 gene network.
• To identify potential therapeutic targets for RTT by prioritizing proteins with co-evolutionary signatures with MECP2.

Main Methods:

• Constructed a MECP2 gene network using 1028 eukaryotic genomes.
• Prioritized proteins with strong co-evolutionary signatures with MECP2.
• Focused on proteins targeted by FDA-approved drugs.

Main Results:

• Identified three promising drug targets: IRAK, KEAP1, and EPOR.
• Two targets (IRAK, KEAP1) have prior links to MECP2 function; one (EPOR) is a novel link.
• FDA-approved drugs (Pacritinib, DMF, EPO) targeting these proteins rescued RTT phenotypes in human neural cells.
• Drug effects converged on Nuclear Factor Kappa B (NF-κB) signaling in inflammation.

Conclusions:

• Comparative genomics can accelerate drug discovery for complex genetic disorders like RTT.
• Identified IRAK, KEAP1, and EPOR as potential therapeutic targets for RTT.
• The NF-κB signaling pathway presents a promising avenue for RTT treatment development.