An RNA interference screen identifies druggable regulators of MeCP2 stability

Area of Science:

• Neuroscience
• Genetics
• Pharmacology

Background:

• Copy number variations in genes, including MECP2, are linked to neurodevelopmental disorders like autism and intellectual disability (ID).
• Altered levels of methyl-CpG-binding protein 2 (MeCP2) cause distinct neurological conditions, such as Rett syndrome (loss-of-function) and MeCP2 duplication syndrome (MDS).
• Current treatments do not exist to clinically adjust MeCP2 levels, despite evidence from animal models suggesting restoration can reverse disease progression.

Purpose of the Study:

• To identify druggable regulators of MeCP2 stability using a genetic screen.
• To validate HIPK2 and PP2A as modulators of MeCP2.
• To investigate the therapeutic potential of targeting PP2A in a mouse model of MDS.

Main Methods:

• Conducted a forward genetic screen of human kinases and phosphatases.
• Validated HIPK2 and PP2A as MeCP2 stabilizers in vivo.
• Utilized pharmacological inhibition of PP2A in a mouse model of MDS.

Main Results:

• HIPK2 and PP2A were identified as regulators of MeCP2 stability.
• Inhibition of PP2A in vivo decreased MeCP2 levels in the nervous system.
• Pharmacological PP2A inhibition ameliorated overexpression and motor deficits in a mouse model of MDS.

Conclusions:

• HIPK2 and PP2A represent potential therapeutic targets for disorders associated with MeCP2 gene dosage alterations.
• Targeting PP2A may offer a strategy to treat MeCP2 duplication syndrome and related neurodevelopmental conditions.
• These findings open new avenues for developing treatments for MeCP2-related disorders.