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    Multimodal Analysis of STRADA Function in Brain Development

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    Author
    Iffland, II, P.H.
    Barnes, A.E.
    Baybis, M.
    Crino, P.B.
    Date
    2020
    Journal
    Frontiers in Cellular Neuroscience
    Publisher
    Frontiers Media S.A.
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.3389/fncel.2020.00122
    Abstract
    mTORopathies are a heterogeneous group of neurological disorders characterized by malformations of cortical development (MCD), enhanced cellular mechanistic target of rapamycin (mTOR) signaling, and epilepsy that results from mutations in mTOR pathway regulatory genes. Homozygous mutations (del exon 9–13) in the pseudokinase STE20-related kinase adaptor alpha (STRAD-α; STRADA), an mTOR modulator, are associated with Pretzel Syndrome (PS), a neurodevelopmental disorder within the Old Order Mennonite Community characterized by megalencephaly, intellectual disability, and intractable epilepsy. To study the cellular mechanisms of STRADA loss, we generated CRISPR-edited Strada mouse N2a cells, a germline mouse Strada knockout (KO−/−) strain, and induced pluripotent stem cell (iPSC)-derived neurons from PS individuals harboring the STRADA founder mutation. Strada KO in vitro leads to enhanced mTOR signaling and iPSC-derived neurons from PS individuals exhibit enhanced cell size and mTOR signaling activation, as well as subtle alterations in electrical firing properties e.g., increased input resistance, a more depolarized resting membrane potential, and decreased threshold for action potential (AP) generation. Strada−/− mice exhibit high rates of perinatal mortality and out of more than 100 litters yielding both WT and heterozygous pups, only eight Strada−/− animals survived past P5. Strada−/− mice are hypotonic and tremulous. Histopathological examination (n = 5 mice) revealed normal gross brain organization and lamination but all had ventriculomegaly. Ectopic neurons were seen in all five Strada−/− brains within the subcortical white matter mirroring what is observed in human PS brain tissue. These distinct experimental platforms demonstrate that STRADA modulates mTOR signaling and is a key regulator of cell size, neuronal excitability, and cortical lamination. Copyright 2020 The Authors.
    Sponsors
    Funding from National Institute of Neurological Disorders and Stroke (NINDS) R01NS094596, R01NS099452, R21NS087181-01, K08NS109289 and a Ravitz Advancement Award from the Department of Pediatrics, Michigan Medicine.
    Keyword
    epilepsy
    iPSC
    megalencephaly
    mouse
    mTOR
    seizure
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85085199060&doi=10.3389%2ffncel.2020.00122&partnerID=40&md5=36c6b6d7d4828ad248831b17fce775cf; http://hdl.handle.net/10713/12904
    ae974a485f413a2113503eed53cd6c53
    10.3389/fncel.2020.00122
    Scopus Count
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    UMB Open Access Articles 2020

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