ArticleThe Journal of clinical investigation2010
STRADalpha deficiency results in aberrant mTORC1 signaling during corticogenesis in humans and mice.
Article in The Journal of clinical investigation, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 74 papers.
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Who cites it
74 citing papers in PubMed, 105 citations in OpenAlex.
- Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE): genetics, mechanisms and precision therapy.Acta neuropathologica · 2026Review
- Antenatal diagnosis and maternal sirolimus treatment of polyhydramnios, megalencephaly, and symptomatic epilepsy (PMSE) syndrome.Pregnancy (Hoboken, N.J.) · 2026Article
- The Clinical Spectrum and Neurodevelopmental Pathogenesis of KPTN-Related Disorder in a Mouse Model.Annals of neurology · 2026Article
- Delayed forebrain excitatory and inhibitory neurogenesis in STRADA-related megalencephaly via mTOR hyperactivity.Stem cell reports · 2026Article
- Mechanistic Target of Rapamycin and Megalencephaly: Novel Research Strategies for Therapeutic Discovery.Epilepsy currents · 2026Article
- Review
- The Evolving Landscape of Therapeutics for Epilepsy in Tuberous Sclerosis Complex.Biomedicines · 2023Review
- The organization and function of the Golgi apparatus in dendrite development and neurological disorders.Genes & diseases · 2023Review
- Altered Extracellular Matrix as an Alternative Risk Factor for Epileptogenicity in Brain Tumors.Biomedicines · 2022Review
- Mechanistic target of rapamycin signaling in human nervous system development and disease.Frontiers in molecular neuroscience · 2022Review
- STRADA-mutant human cortical organoids model megalencephaly and exhibit delayed neuronal differentiation.Developmental neurobiology · 2021Article
- Precision Therapy for Epilepsy Related to Brain Malformations.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2021Review
- Current Approaches and Future Directions for the Treatment of mTORopathies.Developmental neuroscience · 2021Review
- Convergent and Divergent Mechanisms of Epileptogenesis in mTORopathies.Frontiers in neuroanatomy · 2021Review
- The Putative Role of mTOR Inhibitors in Non-tuberous Sclerosis Complex-Related Epilepsy.Frontiers in neurology · 2021Review
- Corrigendum: Convergent and Divergent Mechanisms of Epileptogenesis in mTORopathies.Frontiers in neuroanatomy · 2021Article
- Epilepsy in the mTORopathies: opportunities for precision medicine.Brain communications · 2021Review
- Microglial mTOR is Neuronal Protective and Antiepileptogenic in the Pilocarpine Model of Temporal Lobe Epilepsy.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2020Article
- Sevoflurane Postconditioning Reduces Hypoxia-Reoxygenation Injury in H9C2 Embryonic Rat Cardiomyocytes and Targets the STRADA Gene by Upregulating microRNA-107.Medical science monitor : international medical journal of experimental and clinical research · 2020Article
- Therapeutic role of targeting mTOR signaling and neuroinflammation in epilepsy.Epilepsy research · 2020Review
14 more citing papers are in PubMed but not listed here.
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9 authors at 2 institutions in 1 country.
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Abstract
Polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome (PMSE) is a rare human autosomal-recessive disorder characterized by abnormal brain development, cognitive disability, and intractable epilepsy. It is caused by homozygous deletions of STE20-related kinase adaptor alpha (STRADA). The underlying pathogenic mechanisms of PMSE and the role of STRADA in cortical development remain unknown. Here, we found that a human PMSE brain exhibits cytomegaly, neuronal heterotopia, and aberrant activation of mammalian target of rapamycin complex 1 (mTORC1) signaling. STRADalpha normally binds and exports the protein kinase LKB1 out of the nucleus, leading to suppression of the mTORC1 pathway. We found that neurons in human PMSE cortex exhibited abnormal nuclear localization of LKB1. To investigate this further, we modeled PMSE in mouse neural progenitor cells (mNPCs) in vitro and in developing mouse cortex in vivo by knocking down STRADalpha expression. STRADalpha-deficient mNPCs were cytomegalic and showed aberrant rapamycin-dependent activation of mTORC1 in association with abnormal nuclear localization of LKB1. Consistent with the observations in human PMSE brain, knockdown of STRADalpha in vivo resulted in cortical malformation, enhanced mTORC1 activation, and abnormal nuclear localization of LKB1. Thus, we suggest that the aberrant nuclear accumulation of LKB1 caused by STRADalpha deficiency contributes to hyperactivation of mTORC1 signaling and disruption of neuronal lamination during corticogenesis, and thereby the neurological features associated with PMSE.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.