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An RNA interference screen identifies druggable regulators of MeCP2 stability

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Science Translational Medicine  23 Aug 2017:
Vol. 9, Issue 404, eaaf7588
DOI: 10.1126/scitranslmed.aaf7588

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An HIP strategy for treating MeCP2 disorders

The role of altered gene dosage is increasingly being recognized in neuropsychiatric disorders and intellectual disability (ID). Even a twofold change in the dose of methyl-CpG–binding protein 2 (MeCP2)—either increased or decreased—results in distinct disorders with overlapping features including ID, autistic behavior, and severe motor dysfunction. In a new work, Lombardi et al. identified four regulators of MeCP2 stability and validated regulation of MeCP2 by PP2A and HIPK2 in vivo. They then demonstrated that pharmacological inhibition of PP2A was sufficient to partially rescue MeCP2 overexpression and certain motor abnormalities in a mouse model of MECP2 duplication syndrome.

Abstract

Alterations in gene dosage due to copy number variation are associated with autism spectrum disorder, 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 twofold change in MeCP2 protein—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 can reverse the course of disease, there are currently no U.S. Food and Drug Administration–approved therapies available to clinically modulate MeCP2 abundance. 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, HIPK2 (homeodomain-interacting protein kinase 2) and PP2A (protein phosphatase 2A), were validated as stabilizers of MeCP2 in vivo. Further, pharmacological inhibition of PP2A in vivo reduced MeCP2 in 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.

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