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@ARTICLE{Lenoel:280906,
      author       = {Lenoel, Isadora and Ribon, Matthieu and Lorenc, Félicie
                      and Diebold, Aurélien and Philibert, Clementine E and
                      Robaldo, David and Badsi, Manel and Perronnet, Julianne and
                      Lameth, Julie and Berriat, Felix and Misawa, Hidemi and
                      Coutelier, Marie and Cassel, Raphaelle and Sarrazin, Nadège
                      and Jost-Mousseau, Coline and Bohl, Delphine and Millecamps,
                      Stéphanie and Mallat, Michel and Brenner, David and
                      Weishaupt, Jochen H and Boillée, Séverine and Lobsiger,
                      Christian S},
      title        = {{ALS}/{FTD}-linked {TBK}1 deficiency in microglia induces
                      an aged-like microglial signature and drives social
                      recognition deficits in mice.},
      journal      = {Nature Communications},
      volume       = {16},
      number       = {1},
      issn         = {2041-1723},
      address      = {[London]},
      publisher    = {Springer Nature},
      reportid     = {DZNE-2025-00990},
      pages        = {7951},
      year         = {2025},
      abstract     = {TANK-Binding Kinase 1 (TBK1) is involved in autophagy and
                      immune signaling. Dominant loss-of-function mutations in
                      TBK1 have been linked to Amyotrophic Lateral Sclerosis
                      (ALS), Fronto-temporal dementia (FTD), and ALS/FTD. However,
                      pathogenic mechanisms remain unclear, particularly the
                      cell-type specific disease contributions of TBK1 mutations.
                      Here, we show that deleting Tbk1 from mouse motor neurons
                      does not induce transcriptional stress, despite lifelong
                      signs of autophagy deregulations. Conversely, Tbk1 deletion
                      in microglia alters their homeostasis and reactive
                      responses. In both spinal cord and brain, Tbk1 deletion
                      leads to a pro-inflammatory, primed microglial signature
                      with features of ageing and neurodegeneration. While it does
                      not induce or modify ALS-like motor neuron damage,
                      microglial Tbk1 deletion is sufficient to cause early
                      FTD-like social recognition deficits. This phenotype is
                      linked to focal microglial activation and T cell
                      infiltration in the substantia nigra pars reticulata and
                      pallidum. Our results reveal that part of TBK1-linked FTD
                      disease originates from microglial dysfunction.},
      keywords     = {Animals / Protein Serine-Threonine Kinases: genetics /
                      Protein Serine-Threonine Kinases: deficiency / Protein
                      Serine-Threonine Kinases: metabolism / Microglia: metabolism
                      / Microglia: pathology / Amyotrophic Lateral Sclerosis:
                      genetics / Amyotrophic Lateral Sclerosis: pathology /
                      Amyotrophic Lateral Sclerosis: metabolism / Mice /
                      Frontotemporal Dementia: genetics / Frontotemporal Dementia:
                      metabolism / Frontotemporal Dementia: pathology / Motor
                      Neurons: metabolism / Motor Neurons: pathology / Mice,
                      Knockout / Spinal Cord: pathology / Spinal Cord: metabolism
                      / Male / Autophagy / Disease Models, Animal / Female / Mice,
                      Inbred C57BL / Aging / Brain: pathology / Brain: metabolism
                      / Humans / Protein Serine-Threonine Kinases (NLM Chemicals)
                      / Tbk1 protein, mouse (NLM Chemicals)},
      cin          = {Clinical Study Center (Ulm)},
      ddc          = {500},
      cid          = {I:(DE-2719)5000077},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40858618},
      pmc          = {pmc:PMC12381211},
      doi          = {10.1038/s41467-025-63211-w},
      url          = {https://pub.dzne.de/record/280906},
}