Rapamycin Prevents Seizures After Depletion of STRADA in a Rare Neurodevelopmental Disorder
| Autor: | Jacqueline F. Birnbaum, Kei Okochi, Kevin A. Strauss, Jelte Helfferich, Marianna Baybis, Ksenia A. Orlova, Dmitry A. Goncharov, Whitney E. Parker, Peter B. Crino, Vera P. Krymskaya, William H. Parker |
|---|---|
| Přispěvatelé: | Faculteit Medische Wetenschappen/UMCG |
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Pathology
medicine.medical_specialty ASTROCYTOMAS MIGRATION Population Blotting Western mTORC1 Biology Mechanistic Target of Rapamycin Complex 1 Article Piperazines PATHWAY ACTIVATION Epilepsy Mice Neurodevelopmental disorder Cell Movement Central Nervous System Diseases Pregnancy Seizures medicine Subependymal zone KINASE Animals Humans Megalencephaly TUBEROUS SCLEROSIS COMPLEX education EPILEPSY Cells Cultured Sirolimus education.field_of_study MTOR TOR Serine-Threonine Kinases Cytarabine Imidazoles General Medicine MOUSE MODEL medicine.disease DEVELOPMENTAL BRAIN MALFORMATIONS Immunohistochemistry Multiprotein Complexes Pretzel syndrome Cancer research Female biological phenomena cell phenomena and immunity LYK5 |
| Zdroj: | Science Translational Medicine, 5(182). AMER ASSOC ADVANCEMENT SCIENCE |
| ISSN: | 1946-6234 |
| Popis: | A rare neurodevelopmental disorder in the Old Order Mennonite population called PMSE (polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome; also called Pretzel syndrome) is characterized by infantile-onset epilepsy, neurocognitive delay, craniofacial dysmorphism, and histopathological evidence of heterotopic neurons in subcortical white matter and subependymal regions. PMSE is caused by a homozygous deletion of exons 9 to 13 of the LYK5/STRADA gene, which encodes the pseudokinase STRADA, an upstream inhibitor of mammalian target of rapamycin complex 1 (mTORC1). We show that disrupted pathfinding in migrating mouse neural progenitor cells in vitro caused by STRADA depletion is prevented by mTORC1 inhibition with rapamycin or inhibition of its downstream effector p70 S6 kinase (p70S6K) with the drug PF-4708671 (p70S6Ki). We demonstrate that rapamycin can rescue aberrant cortical lamination and heterotopia associated with STRADA depletion in the mouse cerebral cortex. Constitutive mTORC1 signaling and a migration defect observed in fibroblasts from patients with PMSE were also prevented by mTORC1 inhibition. On the basis of these preclinical findings, we treated five PMSE patients with sirolimus (rapamycin) without complication and observed a reduction in seizure frequency and an improvement in receptive language. Our findings demonstrate a mechanistic link between STRADA loss and mTORC1 hyperactivity in PMSE, and suggest that mTORC1 inhibition may be a potential treatment for PMSE as well as other mTOR-associated neurodevelopmental disorders. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|