An RNA interference screen identifies druggable regulators of MeCP2 stability

Alterations in gene dosage due to copy-number variation (CNV) are associated with autism spectrum disorder (ASD), intellectual disability (ID) and other psychiatric disorders. The nervous system is so acutely sensitive to the dose of methyl-CpG-binding protein 2 (MeCP2) that even a two-fold change in MeCP2 protein level—either increased or decreased—results in distinct disorders with overlapping features including ID, autistic behavior and severe motor dysfunction. Rett syndrome is caused by loss-of-function mutations in MECP2, whereas duplications spanning the MECP2 locus result in MECP2 Duplication Syndrome (MDS) which accounts for ~1% of X-linked ID. Despite evidence from mouse models that restoring MeCP2 levels can reverse the course of disease, there are currently no FDA-approved therapies available to clinically modulate MeCP2 abundance. In this study we used a forward genetic screen against all known human kinases and phosphatases to identify druggable regulators of MeCP2 stability. Two putative modulators of MeCP2 levels, HIPK2 and protein phosphatase PP2A, were validated as stabilizers of MeCP2 in vivo. Further, pharmacological inhibition of PP2A in vivo reduced MeCP2 levels within the nervous system and rescued both overexpression and motor abnormalities in a mouse model of MDS. Our findings reveal potential therapeutic targets for treating disorders of altered MECP2 dosage and establish a potent strategy to identify druggable candidates for the broader category of neurologic disease resulting from CNVs.