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@ARTICLE{Hu:270416,
      author       = {Hu, Yiying and Hruscha, Alexander and Pan, Chenchen and
                      Schifferer, Martina and Schmidt, Michael K and Nuscher,
                      Brigitte and Giera, Martin and Kostidis, Sarantos and
                      Burhan, Özge and van Bebber, Frauke and Edbauer, Dieter and
                      Arzberger, Thomas and Haass, Christian and Schmid, Bettina},
      title        = {{M}is-localization of endogenous {TDP}-43 leads to
                      {ALS}-like early-stage metabolic dysfunction and progressive
                      motor deficits.},
      journal      = {Molecular neurodegeneration},
      volume       = {19},
      number       = {1},
      issn         = {1750-1326},
      address      = {London},
      publisher    = {Biomed Central},
      reportid     = {DZNE-2024-00796},
      pages        = {50},
      year         = {2024},
      abstract     = {The key pathological signature of ALS/ FTLD is the
                      mis-localization of endogenous TDP-43 from the nucleus to
                      the cytoplasm. However, TDP-43 gain of function in the
                      cytoplasm is still poorly understood since TDP-43 animal
                      models recapitulating mis-localization of endogenous TDP-43
                      from the nucleus to the cytoplasm are missing.CRISPR/Cas9
                      technology was used to generate a zebrafish line (called
                      CytoTDP), that mis-locates endogenous TDP-43 from the
                      nucleus to the cytoplasm. Phenotypic characterization of
                      motor neurons and the neuromuscular junction was performed
                      by immunostaining, microglia were immunohistochemically
                      localized by whole-mount tissue clearing and muscle
                      ultrastructure was analyzed by scanning electron microscopy.
                      Behavior was investigated by video tracking and quantitative
                      analysis of swimming parameters. RNA sequencing was used to
                      identify mis-regulated pathways with validation by molecular
                      analysis.CytoTDP fish have early larval phenotypes
                      resembling clinical features of ALS such as progressive
                      motor defects, neurodegeneration and muscle atrophy. Taking
                      advantage of zebrafish's embryonic development that solely
                      relys on yolk usage until 5 days post fertilization, we
                      demonstrated that microglia proliferation and activation in
                      the hypothalamus is independent from food intake. By
                      comparing CytoTDP to a previously generated TDP-43 knockout
                      line, transcriptomic analyses revealed that mis-localization
                      of endogenous TDP-43, rather than TDP-43 nuclear loss of
                      function, leads to early onset metabolic dysfunction.The new
                      TDP-43 model mimics the ALS/FTLD hallmark of progressive
                      motor dysfunction. Our results suggest that functional
                      deficits of the hypothalamus, the metabolic regulatory
                      center, might be the primary cause of weight loss in ALS
                      patients. Cytoplasmic gain of function of endogenous TDP-43
                      leads to metabolic dysfunction in vivo that are reminiscent
                      of early ALS clinical non-motor metabolic alterations. Thus,
                      the CytoTDP zebrafish model offers a unique opportunity to
                      identify mis-regulated targets for therapeutic intervention
                      early in disease progression.},
      keywords     = {Animals / Zebrafish / Amyotrophic Lateral Sclerosis:
                      metabolism / Amyotrophic Lateral Sclerosis: pathology /
                      Amyotrophic Lateral Sclerosis: genetics / DNA-Binding
                      Proteins: metabolism / DNA-Binding Proteins: genetics /
                      Disease Models, Animal / Motor Neurons: metabolism / Motor
                      Neurons: pathology / Zebrafish Proteins: metabolism /
                      Zebrafish Proteins: genetics / Animals, Genetically Modified
                      / Neuromuscular Junction: metabolism / Neuromuscular
                      Junction: pathology / ALS (Other) / Animal model (Other) /
                      Hypothalamus (Other) / Metabolic dysfunction (Other) /
                      Neurodegeneration (Other) / TDP-43 (Other) / Zebrafish
                      (Other) / DNA-Binding Proteins (NLM Chemicals) / Zebrafish
                      Proteins (NLM Chemicals) / Tardbp protein, zebrafish (NLM
                      Chemicals)},
      cin          = {AG Schmid / AG Misgeld / AG Edbauer / AG Haass},
      ddc          = {570},
      cid          = {I:(DE-2719)1140002 / I:(DE-2719)1110000-4 /
                      I:(DE-2719)1110004 / I:(DE-2719)1110007},
      pnm          = {352 - Disease Mechanisms (POF4-352) / 351 - Brain Function
                      (POF4-351)},
      pid          = {G:(DE-HGF)POF4-352 / G:(DE-HGF)POF4-351},
      typ          = {PUB:(DE-HGF)16},
      pmc          = {pmc:PMC11188230},
      pubmed       = {pmid:38902734},
      doi          = {10.1186/s13024-024-00735-7},
      url          = {https://pub.dzne.de/record/270416},
}