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@ARTICLE{Zillich:305359,
      author       = {L. Zillich$^*$ and M. Gasparotto$^*$ and A. C. Rossetti$^*$
                      and O. Fechtner$^*$ and C. Maillard and A. Hoffrichter$^*$
                      and E. Zillich and A. Jabali$^*$ and F. Marsoner$^*$ and A.
                      Artioli$^*$ and R. Wilkens$^*$ and C. B. Schroeter and A.
                      Hentschel and S. H. Witt and N. Melzer and S. G. Meuth and
                      T. Ruck and P. Koch$^*$ and A. Roos and N. Bahi-Buisson and
                      F. Francis and J. Ladewig$^*$},
      title        = {{C}apturing disease severity in {LIS}1-lissencephaly
                      reveals proteostasis dysregulation in patient-derived
                      forebrain organoids.},
      journal      = {Nature Communications},
      volume       = {16},
      number       = {1},
      issn         = {2041-1723},
      address      = {[London]},
      publisher    = {Springer Nature},
      reportid     = {DKFZ-2025-02103},
      pages        = {9091},
      year         = {2025},
      note         = {#EA:A340#LA:A340#},
      abstract     = {LIS1-lissencephaly is a neurodevelopmental disorder marked
                      by reduced cortical folding and severe neurological
                      impairment. Although all cases result from heterozygous
                      mutations in the LIS1 gene, patients present a broad
                      spectrum of severity. Here, we use patient-derived forebrain
                      organoids representing mild, moderate, and severe
                      LIS1-lissencephaly to uncover mechanisms underlying this
                      variability. We show that LIS1 protein levels vary across
                      patient lines and partly correlate with clinical severity,
                      indicating mutation-specific effects on protein function.
                      Integrated morphological, transcriptomic, and proteomic
                      analyses reveal progressive changes in neural progenitor
                      homeostasis and neurogenesis that scale with severity.
                      Mechanistically, microtubule destabilization disrupts
                      cell-cell junctions and impairs WNT signaling, and defects
                      in protein homeostasis, causing stress from misfolded
                      proteins, emerge as key severity-linked pathways.
                      Pharmacological inhibition of mTORC1 partially rescues these
                      defects. Our findings demonstrate that patient-derived
                      organoids can model disease severity, enabling mechanistic
                      dissection and guiding targeted strategies in
                      neurodevelopmental disorders.},
      keywords     = {Organoids: metabolism / Organoids: pathology / Humans /
                      Prosencephalon: metabolism / Prosencephalon: pathology /
                      Proteostasis: genetics / Microtubule-Associated Proteins:
                      genetics / Microtubule-Associated Proteins: metabolism /
                      Lissencephaly: genetics / Lissencephaly: metabolism /
                      Lissencephaly: pathology /
                      1-Alkyl-2-acetylglycerophosphocholine Esterase: genetics /
                      1-Alkyl-2-acetylglycerophosphocholine Esterase: metabolism /
                      Mutation / Neurogenesis: genetics / Mechanistic Target of
                      Rapamycin Complex 1: metabolism / Mechanistic Target of
                      Rapamycin Complex 1: antagonists $\&$ inhibitors / Severity
                      of Illness Index / Wnt Signaling Pathway / Proteomics /
                      Neural Stem Cells: metabolism / Microtubules: metabolism /
                      Female / Microtubule-Associated Proteins (NLM Chemicals) /
                      PAFAH1B1 protein, human (NLM Chemicals) /
                      1-Alkyl-2-acetylglycerophosphocholine Esterase (NLM
                      Chemicals) / Mechanistic Target of Rapamycin Complex 1 (NLM
                      Chemicals)},
      cin          = {A340},
      ddc          = {500},
      cid          = {I:(DE-He78)A340-20160331},
      pnm          = {311 - Zellbiologie und Tumorbiologie (POF4-311)},
      pid          = {G:(DE-HGF)POF4-311},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41083500},
      doi          = {10.1038/s41467-025-64980-0},
      url          = {https://inrepo02.dkfz.de/record/305359},
}