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@ARTICLE{Raas:277532,
      author       = {Raas, Quentin and Haouy, Gregoire and de Calbiac, Hortense
                      and Pasho, Elena and Marian, Anca and Guerrera, Ida Chiara
                      and Rosello, Marion and Oeckl, Patrick and Del Bene, Filippo
                      and Catanese, Alberto and Ciura, Sorana and Kabashi, Edor},
      title        = {{TBK}1 is involved in programmed cell death and
                      {ALS}-related pathways in novel zebrafish models.},
      journal      = {Cell death discovery},
      volume       = {11},
      number       = {1},
      issn         = {2058-7716},
      address      = {London},
      publisher    = {Nature Publishing Group},
      reportid     = {DZNE-2025-00428},
      pages        = {98},
      year         = {2025},
      abstract     = {Pathogenic mutations within the TBK1 gene leading to
                      haploinsufficiency are causative of amyotrophic lateral
                      sclerosis (ALS). This gene is linked to autophagy and
                      inflammation, two cellular mechanisms reported to be
                      dysregulated in ALS patients, although its functional role
                      in the pathogenesis could involve other players. We targeted
                      the TBK1 ortholog in zebrafish, an optimal vertebrate model
                      for investigating genetic defects in neurological disorders.
                      We generated zebrafish models with invalidating tbk1
                      mutations using CRISPR-Cas9 or tbk1 knockdown models using
                      antisense morpholino oligonucleotide (AMO). The early motor
                      phenotype of zebrafish injected with tbk1 AMO beginning at 2
                      days post fertilization (dpf) is associated with the
                      degeneration of motor neurons. In parallel, CRISPR-induced
                      tbk1 mutants exhibit impaired motor function beginning at 5
                      dpf and increased lethality beginning at 9 dpf. A
                      metabolomic analysis showed an association between tbk1 loss
                      and severe dysregulation of nicotinamide metabolism, and
                      incubation with nicotinamide riboside rescued the motor
                      behavior of tbk1 mutant zebrafish. Furthermore, a proteomic
                      analysis revealed increased levels of inflammatory markers
                      and dysregulation of programmed cell death pathways.
                      Necroptosis appeared to be strongly activated in TBK1 fish,
                      and larvae treated with the necroptosis inhibitor
                      necrosulfonamide exhibited improved survival. Finally, a
                      combined analysis of mutant zebrafish and TBK1-mutant human
                      motor neurons revealed dysregulation of the KEGG pathway
                      'ALS', with disrupted nuclear-cytoplasmic transport and
                      increased expression of STAT1. These findings point toward a
                      major role for necroptosis in the degenerative features and
                      premature lethality observed in tbk1 mutant zebrafish.
                      Overall, the novel tbk1-deficient zebrafish models offer a
                      great opportunity to better understand the cascade of events
                      leading from the loss of tbk1 expression to the onset of
                      motor deficits, with involvement of a metabolic defect and
                      increased cell death, and for the development of novel
                      therapeutic avenues for ALS and related neuromuscular
                      diseases.},
      cin          = {AG Öckl},
      ddc          = {610},
      cid          = {I:(DE-2719)5000073},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40075110},
      doi          = {10.1038/s41420-025-02374-3},
      url          = {https://pub.dzne.de/record/277532},
}