Rapamycin prevents seizures after depletion of STRADA in a rare neurodevelopmental disorder

Area of Science:

• Neurodevelopmental disorders
• Genetics
• Molecular biology

Background:

• Polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome (PMSE), also known as Pretzel syndrome, is a rare neurodevelopmental disorder.
• PMSE presents with infantile epilepsy, cognitive delay, craniofacial abnormalities, and neuronal heterotopia.
• The condition arises from a homozygous deletion in the LYK5/STRADA gene, affecting the STRADA protein, an inhibitor of mTORC1 signaling.

Purpose of the Study:

• To investigate the mechanistic link between STRADA loss and mTORC1 hyperactivity in PMSE.
• To evaluate the therapeutic potential of mTORC1 inhibition in PMSE and related neurodevelopmental disorders.

Main Methods:

• Studied neural progenitor cell migration in vitro following STRADA depletion, testing rapamycin and PF-4708671 (p70S6Ki).
• Assessed the rescue of cortical lamination and heterotopia in mouse models with STRADA depletion using rapamycin.
• Examined mTORC1 signaling and fibroblast migration in PMSE patients, with and without mTORC1 inhibition.

Main Results:

• STRADA depletion-induced neural progenitor cell migration defects were rescued by inhibiting mTORC1 or p70S6K.
• Rapamycin treatment corrected aberrant cortical lamination and heterotopia in mice with STRADA depletion.
• Constitutive mTORC1 signaling and migration defects in PMSE patient fibroblasts were ameliorated by mTORC1 inhibition.

Conclusions:

• STRADA loss leads to mTORC1 hyperactivity, causing neurodevelopmental defects in PMSE.
• Preclinical findings support mTORC1 inhibition as a potential therapeutic strategy for PMSE.
• Sirolimus (rapamycin) treatment in five PMSE patients reduced seizures and improved language, validating mTORC1 inhibition as a treatment approach.