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@ARTICLE{LaClair:153340,
      author       = {LaClair, Katherine D and Zhou, Qihui and Michaelsen, Meike
                      and Wefers, Benedikt and Brill, Monika S and Janjic,
                      Aleksandar and Rathkolb, Birgit and Farny, Daniel and Cygan,
                      Mikolaj and de Angelis, Martin Hrabe and Wurst, Wolfgang and
                      Neumann, Manuela and Enard, Wolfgang and Misgeld, Thomas and
                      Arzberger, Thomas and Edbauer, Dieter},
      title        = {{C}ongenic expression of poly-{GA} but not poly-{PR} in
                      mice triggers selective neuron loss and interferon responses
                      found in {C}9orf72 {ALS}.},
      journal      = {Acta neuropathologica},
      volume       = {140},
      number       = {2},
      issn         = {1432-0533},
      address      = {Heidelberg},
      publisher    = {Springer},
      reportid     = {DZNE-2020-01337},
      pages        = {121 - 142},
      year         = {2020},
      abstract     = {Expansion of a (G4C2)n repeat in C9orf72 causes amyotrophic
                      lateral sclerosis (ALS) and frontotemporal dementia (FTD),
                      but the link of the five repeat-encoded dipeptide repeat
                      (DPR) proteins to neuroinflammation, TDP-43 pathology, and
                      neurodegeneration is unclear. Poly-PR is most toxic in
                      vitro, but poly-GA is far more abundant in patients. To
                      directly compare these in vivo, we created congenic poly-GA
                      and poly-PR mice. $40\%$ of poly-PR mice were affected with
                      ataxia and seizures, requiring euthanasia by 6 weeks of
                      age. The remaining poly-PR mice were asymptomatic at
                      14 months of age, likely due to an $80\%$ reduction of the
                      transgene mRNA in this subgroup. In contrast, all poly-GA
                      mice showed selective neuron loss, inflammation, as well as
                      muscle denervation and wasting requiring euthanasia before
                      7 weeks of age. In-depth analysis of peripheral organs and
                      blood samples suggests that peripheral organ failure does
                      not drive these phenotypes. Although transgene mRNA levels
                      were similar between poly-GA and affected poly-PR mice,
                      poly-GA aggregated far more abundantly than poly-PR in the
                      CNS and was also found in skeletal muscle. In addition,
                      TDP-43 and other disease-linked RNA-binding proteins
                      co-aggregated in rare nuclear inclusions in the hippocampus
                      and frontal cortex only in poly-GA mice. Transcriptome
                      analysis revealed activation of an interferon-responsive
                      pro-inflammatory microglial signature in end-stage poly-GA
                      but not poly-PR mice. This signature was also found in all
                      ALS patients and enriched in C9orf72 cases. In summary, our
                      rigorous comparison of poly-GA and poly-PR toxicity in vivo
                      indicates that poly-GA, but not poly-PR at the same mRNA
                      expression level, promotes interferon responses in C9orf72
                      disease and contributes to TDP-43 abnormalities and neuron
                      loss selectively in disease-relevant regions.},
      keywords     = {Amyotrophic Lateral Sclerosis: genetics / Amyotrophic
                      Lateral Sclerosis: immunology / Amyotrophic Lateral
                      Sclerosis: pathology / Animals / C9orf72 Protein: genetics /
                      DNA Repeat Expansion: genetics / Disease Models, Animal /
                      Interferons: biosynthesis / Mice / Mice, Transgenic / Nerve
                      Degeneration: genetics / Nerve Degeneration: immunology /
                      Nerve Degeneration: pathology / Neurons: pathology},
      cin          = {AG Edbauer / AG Wurst / AG Heneka1 ; AG Heneka 1 / AG
                      Neumann / AG Misgeld / Neuropathology / Brainbank / AG Zhou},
      ddc          = {610},
      cid          = {I:(DE-2719)1110004 / I:(DE-2719)1140001 /
                      I:(DE-2719)1011301 / I:(DE-2719)1210003 /
                      I:(DE-2719)1110000-4 / I:(DE-2719)1140013 /
                      I:(DE-2719)5000080},
      pnm          = {342 - Disease Mechanisms and Model Systems (POF3-342) / 344
                      - Clinical and Health Care Research (POF3-344) / 341 -
                      Molecular Signaling (POF3-341)},
      pid          = {G:(DE-HGF)POF3-342 / G:(DE-HGF)POF3-344 /
                      G:(DE-HGF)POF3-341},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:32562018},
      pmc          = {pmc:PMC7360660},
      doi          = {10.1007/s00401-020-02176-0},
      url          = {https://pub.dzne.de/record/153340},
}