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@ARTICLE{Grass:271722,
      author       = {Grass, Tobias and Dokuzluoglu, Zeynep and Buchner, Felix
                      and Rosignol, Ines and Thomas, Joshua and Caldarelli,
                      Antonio and Dalinskaya, Anna and Becker, Jutta and Rost,
                      Fabian and Marass, Michele and Wirth, Brunhilde and Beyer,
                      Marc and Bonaguro, Lorenzo and Rodriguez-Muela, Natalia},
      title        = {{I}sogenic patient-derived organoids reveal early
                      neurodevelopmental defects in spinal muscular atrophy
                      initiation.},
      journal      = {Cell reports / Medicine},
      volume       = {5},
      number       = {8},
      issn         = {2666-3791},
      address      = {Maryland Heights, MO},
      publisher    = {Elsevier},
      reportid     = {DZNE-2024-01074},
      pages        = {101659},
      year         = {2024},
      abstract     = {Whether neurodevelopmental defects underlie postnatal
                      neuronal death in neurodegeneration is an intriguing
                      hypothesis only recently explored. Here, we focus on spinal
                      muscular atrophy (SMA), a neuromuscular disorder caused by
                      reduced survival of motor neuron (SMN) protein levels
                      leading to spinal motor neuron (MN) loss and muscle wasting.
                      Using the first isogenic patient-derived induced pluripotent
                      stem cell (iPSC) model and a spinal cord organoid (SCO)
                      system, we show that SMA SCOs exhibit abnormal morphological
                      development, reduced expression of early neural progenitor
                      markers, and accelerated expression of MN progenitor and MN
                      markers. Longitudinal single-cell RNA sequencing reveals
                      marked defects in neural stem cell specification and fewer
                      MNs, favoring mesodermal progenitors and muscle cells, a
                      bias also seen in early SMA mouse embryos. Surprisingly,
                      SMN2-to-SMN1 conversion does not fully reverse these
                      developmental abnormalities. These suggest that early
                      neurodevelopmental defects may underlie later MN
                      degeneration, indicating that postnatal SMN-increasing
                      interventions might not completely amend SMA pathology in
                      all patients.},
      keywords     = {Organoids: pathology / Organoids: metabolism / Humans /
                      Muscular Atrophy, Spinal: pathology / Muscular Atrophy,
                      Spinal: genetics / Muscular Atrophy, Spinal: metabolism /
                      Induced Pluripotent Stem Cells: metabolism / Induced
                      Pluripotent Stem Cells: pathology / Motor Neurons: pathology
                      / Motor Neurons: metabolism / Survival of Motor Neuron 1
                      Protein: genetics / Survival of Motor Neuron 1 Protein:
                      metabolism / Survival of Motor Neuron 2 Protein: genetics /
                      Survival of Motor Neuron 2 Protein: metabolism / Animals /
                      Mice / Spinal Cord: pathology / Spinal Cord: metabolism /
                      Neural Stem Cells: metabolism / Neural Stem Cells: pathology
                      / isogenic SMA model (Other) / neurodevelopmental defects
                      (Other) / neuromesodermal progenitors (Other) / organoids
                      (Other) / spinal cord (Other) / Survival of Motor Neuron 1
                      Protein (NLM Chemicals) / Survival of Motor Neuron 2 Protein
                      (NLM Chemicals) / SMN2 protein, human (NLM Chemicals) / SMN1
                      protein, human (NLM Chemicals)},
      cin          = {AG Rodriguez-Muela / AG Beyer / AG Schultze / PRECISE},
      ddc          = {610},
      cid          = {I:(DE-2719)1713001 / I:(DE-2719)1013035 /
                      I:(DE-2719)1013038 / I:(DE-2719)1013031},
      pnm          = {352 - Disease Mechanisms (POF4-352) / 351 - Brain Function
                      (POF4-351) / 354 - Disease Prevention and Healthy Aging
                      (POF4-354)},
      pid          = {G:(DE-HGF)POF4-352 / G:(DE-HGF)POF4-351 /
                      G:(DE-HGF)POF4-354},
      experiment   = {EXP:(DE-2719)PRECISE-20190321},
      typ          = {PUB:(DE-HGF)16},
      pmc          = {pmc:PMC11384962},
      pubmed       = {pmid:39067446},
      doi          = {10.1016/j.xcrm.2024.101659},
      url          = {https://pub.dzne.de/record/271722},
}