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    Cellular aggregation is an mTOR-dependent phenotype in malformations of cortical development (MCD). This finding, observed in gene-edited cells and human tissues, implicates mTOR signaling in epilepsy.

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    Area of Science:

    • Neuroscience
    • Molecular Biology
    • Genetics

    Background:

    • Malformations of cortical development (MCD) linked to mTOR pathway genes (MPGs) are a major cause of drug-resistant epilepsy.
    • MPG-associated MCD often exhibits cytomegaly, cortical dyslamination, and neuronal aggregates.

    Purpose of the Study:

    • To investigate whether cellular aggregation is an mTOR-dependent phenotype in MPG-associated MCD.
    • To identify molecular mechanisms underlying cellular aggregation in MCD.

    Main Methods:

    • CRISPR/Cas9 gene knockout of MPGs (Tsc2, Nprl3, Stradα, Kptn) in N2a cells.
    • Western blotting for phosphorylated ribosomal S6 protein (PS6) to assess mTOR activation.
    • Timelapse live-cell imaging, cell proliferation, and cell death assays.
    • Liquid chromatography-mass spectrometry (LC-MS/MS) for proteomic analysis of aggregates.
    • Immunohistochemical staining of human MCD brain tissue for PS6.

    Main Results:

    • All knockout lines formed multi-cell aggregates in vitro, which were abolished by mTORC1 inhibition (rapamycin).
    • Aggregation was independent of cell proliferation, apoptosis, necrosis, or extracellular DNA.
    • Proteomic analysis revealed altered expression of adhesion molecules, cytoskeletal proteins, and protein processing/transport factors in aggregates.
    • Human MCD tissues showed increased PS6 staining in neuronal clusters.

    Conclusions:

    • Aberrant cellular aggregation is an mTOR-dependent phenotype in MPG-associated MCD.
    • Altered expression of adhesion molecules may contribute to abnormal cell aggregation and cortical lamination in MCD.
    • These findings provide insights into the pathogenesis of epilepsy in MCD and suggest potential therapeutic targets.