STRADA, neuronal migration and epilepsy
Loss of STRADA causes PMSE, or Pretzel Syndrome, a severe childhood epilepsy. We are separating what STRADA loss does through mTOR from what it does independently of it, and asking what a cortex becomes when its inhibitory interneurons never arrive.
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STRADA is an upstream inhibitor of mTORC1, and rapamycin acts on that arm. How much of the phenotype runs through mTOR, and how much through mTOR-independent roles of STRADA inside the migrating neuron itself, is the question we are working on: the two predict different windows for treatment and different drugs. We follow excitatory and inhibitory populations separately after in utero CRISPR knockout, because losing interneurons takes inhibition out of a cortex that is already miswired, and that shortfall is what a seizure-generating network is built on.
Patient-derived iPSCs let us ask the same question in human cells. We generate STRADA-deficient neurons from them and follow the mechanism of migration down to the patterns of cytoskeletal arrangement that move a cell along its track.
PMSE stands for polyhydramnios, megalencephaly and symptomatic epilepsy. It is most common in the Old Order Mennonite population and causes drug-resistant infantile seizures and cognitive impairment. We work with PMSE families and clinicians at the Clinic for Special Children in Lancaster County, Pennsylvania.
