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@ARTICLE{Jones:303118,
      author       = {M. S. O. Jones and S. Lindlar and J. Ludwig and R. Waltes
                      and A. Kumar and S. V Brauchitsch and A. Rossi and E.
                      Ullrich$^*$ and S. Momma and C. M. Freitag and J. K.
                      Hefendehl and K. M. Klein and F. Rosenow and D. Haslinger
                      and A. G. Chiocchetti},
      title        = {{T}he transcriptomic signature of {DEPDC}5 {KO} induced
                      m{TOR} hyperactivation in human neurons and its response to
                      rapamycin treatment.},
      journal      = {Epilepsia},
      volume       = {nn},
      issn         = {0013-9580},
      address      = {Oxford [u.a.]},
      publisher    = {Wiley-Blackwell},
      reportid     = {DKFZ-2025-01537},
      pages        = {nn},
      year         = {2025},
      note         = {epub},
      abstract     = {Mutations of the DEP Domain Containing 5 gene (DEPDC5), a
                      mechanistic Target of Rapamycin (mTOR) inhibitor involved in
                      amino acid sensing, are associated with neurological
                      diseases such as epilepsy and/or autism spectrum disorder
                      (ASD). Loss of DEPDC5 impacts early neuronal development via
                      mTOR hyperactivity. Although, in the
                      mTOR-hyperactivity-associated syndrome tuberous sclerosis,
                      mTOR inhibitors have proven to be beneficial in treating
                      epilepsy, ASD-associated symptoms are ameliorated only
                      partially. Similarly, the mTOR inhibitor rapamycin (RAPA)
                      only partially rescues phenotypes induced by loss of DEPDC5
                      in animal models, suggesting some pathological mechanisms
                      independent of mTOR.We dissected these mechanisms by
                      identifying the DEPDC5-associated gene networks and how they
                      are targeted by RAPA in an isogenic primary human neural
                      progenitor (phNPC) DEPDC5 knock-out cell model.We confirm
                      that loss of DEPDC5 leads to hyperactivation of mTOR,
                      paralleled by altered expression of mTOR-associated genes.
                      These effects were partially (up to $33\%$ of genes)
                      attenuated by RAPA treatment applying a clinically
                      comparable concentration. We did not observe an association
                      of the differentially expressed genes with ASD or epilepsy
                      risk genes in general. However, we identified a significant
                      association with gene networks known to be differentially
                      regulated in cortex samples of individuals with ASD, which
                      were still significantly deregulated after RAPA treatment.
                      Furthermore, genes not rescued in differentiated neurons
                      were specifically associated with synaptic pruning and early
                      cortical development. The observed increase in neuronal
                      markers was confirmed morphologically. RAPA treatment
                      recovered the increased differentiation but not the
                      morphological changes.These new insights on the human gene
                      network of DEPDC5 show evidence for pathological mechanisms
                      that are not attenuated by the currently administered RAPA
                      concentrations or that are independent of mTOR. These
                      mechanisms should be considered as potential targets for
                      future therapies.},
      keywords     = {ASD (Other) / comorbidities (Other) / epilepsy (Other) /
                      human cell model (Other) / neural progenitor cells (Other) /
                      transcriptomics (Other)},
      cin          = {FM01},
      ddc          = {610},
      cid          = {I:(DE-He78)FM01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40704780},
      doi          = {10.1111/epi.18549},
      url          = {https://inrepo02.dkfz.de/record/303118},
}