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@ARTICLE{Brenner:268729,
      author       = {Brenner, David and Sieverding, Kirsten and Srinidhi,
                      Jahnavi and Zellner, Susanne and Secker, Christopher and
                      Yilmaz, Rüstem and Dyckow, Julia and Amr, Shady and
                      Ponomarenko, Anna and Tunaboylu, Esra and Douahem, Yasmin
                      and Schlag, Joana S and Rodriguez Martinez, Lucia and
                      Kislinger, Georg and Niemann, Cornelia and Nalbach, Karsten
                      and Ruf, Wolfgang P and Uhl, Jonathan and Hollenbeck,
                      Johanna and Schirmer, Lucas and Catanese, Alberto and
                      Lobsiger, Christian S and Danzer, Karin M and
                      Yilmazer-Hanke, Deniz and Münch, Christian and Koch,
                      Philipp and Freischmidt, Axel-Dieter and Fetting, Martina
                      and Behrends, Christian and Parlato, Rosanna and Weishaupt,
                      Jochen H},
      title        = {{A} {TBK}1 variant causes autophagolysosomal and motoneuron
                      pathology without neuroinflammation in mice.},
      journal      = {Journal of experimental medicine},
      volume       = {221},
      number       = {5},
      issn         = {0022-1007},
      address      = {New York, NY},
      publisher    = {Rockefeller Univ. Press},
      reportid     = {DZNE-2024-00305},
      pages        = {e20221190},
      year         = {2024},
      abstract     = {Heterozygous mutations in the TBK1 gene can cause
                      amyotrophic lateral sclerosis (ALS) and frontotemporal
                      dementia (FTD). The majority of TBK1-ALS/FTD patients carry
                      deleterious loss-of-expression mutations, and it is still
                      unclear which TBK1 function leads to neurodegeneration. We
                      investigated the impact of the pathogenic TBK1 missense
                      variant p.E696K, which does not abolish protein expression,
                      but leads to a selective loss of TBK1 binding to the
                      autophagy adaptor protein and TBK1 substrate optineurin.
                      Using organelle-specific proteomics, we found that in a
                      knock-in mouse model and human iPSC-derived motor neurons,
                      the p.E696K mutation causes presymptomatic onset of
                      autophagolysosomal dysfunction in neurons precipitating the
                      accumulation of damaged lysosomes. This is followed by a
                      progressive, age-dependent motor neuron disease. Contrary to
                      the phenotype of mice with full Tbk1 knock-out,
                      RIPK/TNF-α-dependent hepatic, neuronal necroptosis, and
                      overt autoinflammation were not detected. Our in vivo
                      results indicate autophagolysosomal dysfunction as a trigger
                      for neurodegeneration and a promising therapeutic target in
                      TBK1-ALS/FTD.},
      keywords     = {Animals / Humans / Mice / Amyotrophic Lateral Sclerosis:
                      pathology / Frontotemporal Dementia: genetics /
                      Frontotemporal Dementia: metabolism / Frontotemporal
                      Dementia: pathology / Motor Neurons: pathology / Mutation /
                      Neuroinflammatory Diseases / Phosphorylation / Protein
                      Serine-Threonine Kinases: genetics / Protein
                      Serine-Threonine Kinases: metabolism / Protein
                      Serine-Threonine Kinases (NLM Chemicals) / TBK1 protein,
                      human (NLM Chemicals) / Tbk1 protein, mouse (NLM Chemicals)},
      cin          = {AG Simons / AG Misgeld / AG Danzer},
      ddc          = {610},
      cid          = {I:(DE-2719)1110008 / I:(DE-2719)1110000-4 /
                      I:(DE-2719)5000072},
      pnm          = {351 - Brain Function (POF4-351) / 352 - Disease Mechanisms
                      (POF4-352)},
      pid          = {G:(DE-HGF)POF4-351 / G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:38517332},
      pmc          = {pmc:PMC10959724},
      doi          = {10.1084/jem.20221190},
      url          = {https://pub.dzne.de/record/268729},
}