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@ARTICLE{Schludi:138124,
      author       = {Schludi, Martin H and May, Stephanie and Grässer,
                      Friedrich A and Rentzsch, Kristin and Kremmer, Elisabeth and
                      Küpper, Clemens and Klopstock, Thomas and Degeneration,
                      German Consortium for Frontotemporal Lobar and Alliance,
                      Bavarian Brain Banking and Arzberger, Thomas and Edbauer,
                      Dieter and Danek, Adrian and Diehl-Schmid, Janine and
                      Fassbender, Klaus and Förstl, Hans and Kornhuber, Johannes
                      and Otto, Markus and Ceballos-Baumann, Andres and Dieterich,
                      Marianne and Feuerecker, Regina and Giese, Armin and
                      Klünemann, Hans and Kurz, Alexander and Levin, Johannes and
                      Lorenzl, Stefan and Meyer, Thomas and Nübling, Georg and
                      Roeber, Sigrun},
      title        = {{D}istribution of dipeptide repeat proteins in cellular
                      models and {C}9orf72 mutation cases suggests link to
                      transcriptional silencing.},
      journal      = {Acta neuropathologica},
      volume       = {130},
      number       = {4},
      issn         = {0001-6322},
      address      = {Heidelberg},
      publisher    = {Springer},
      reportid     = {DZNE-2020-04446},
      pages        = {537-555},
      year         = {2015},
      abstract     = {A massive expansion of a GGGGCC repeat upstream of the
                      C9orf72 coding region is the most common known cause of
                      amyotrophic lateral sclerosis and frontotemporal dementia.
                      Despite its intronic localization and lack of a canonical
                      start codon, both strands are translated into aggregating
                      dipeptide repeat (DPR) proteins: poly-GA, poly-GP, poly-GR,
                      poly-PR and poly-PA. To address conflicting findings on the
                      predominant toxicity of the different DPR species in model
                      systems, we compared the expression pattern of the DPR
                      proteins in rat primary neurons and postmortem brain and
                      spinal cord of C9orf72 mutation patients. Only poly-GA
                      overexpression closely mimicked the p62-positive neuronal
                      cytoplasmic inclusions commonly observed for all DPR
                      proteins in patients. In contrast, overexpressed poly-GR and
                      poly-PR formed nucleolar p62-negative inclusions. In
                      patients, most of the less common neuronal intranuclear DPR
                      inclusions were para-nucleolar and p62 positive. Neuronal
                      nucleoli in C9orf72 cases showed normal size and morphology
                      regardless of the presence of poly-GR and poly-PR inclusions
                      arguing against widespread nucleolar stress, reported in
                      cellular models. Colocalization of para-nucleolar DPR
                      inclusions with heterochromatin and a marker of
                      transcriptional repression (H3K9me2) indicates a link to
                      gene transcription. In contrast, we detected numerous
                      intranuclear DPR inclusions not associated with nucleolar
                      structures in ependymal and subependymal cells. In patients,
                      neuronal inclusions of poly-GR, poly-GP and the poly-GA
                      interacting protein Unc119 were less abundant than poly-GA
                      inclusions, but showed similar regional and subcellular
                      distribution. Regardless of neurodegeneration, all
                      inclusions were most abundant in neocortex, hippocampus and
                      thalamus, with few inclusions in brain stem and spinal cord.
                      In the granular cell layer of the cerebellum, poly-GA and
                      Unc119 inclusions were significantly more abundant in cases
                      with FTLD than in cases with MND and FTLD/MND. Poly-PR
                      inclusions were rare throughout the brain but significantly
                      more abundant in the CA3/4 region of FTLD cases than in MND
                      cases. Thus, although DPR distribution is not correlated
                      with neurodegeneration spatially, it correlates with
                      neuropathological subtypes.},
      keywords     = {Adaptor Proteins, Signal Transducing: metabolism / Adult /
                      Aged / Animals / Brain: metabolism / Brain: pathology /
                      C9orf72 Protein / Cell Nucleolus: metabolism / Cell
                      Nucleolus: pathology / Cohort Studies / DNA Repeat Expansion
                      / Frontotemporal Lobar Degeneration: complications /
                      Frontotemporal Lobar Degeneration: genetics / Frontotemporal
                      Lobar Degeneration: metabolism / Frontotemporal Lobar
                      Degeneration: pathology / Gene Silencing / Humans /
                      Inclusion Bodies: metabolism / Inclusion Bodies: pathology /
                      Middle Aged / Motor Neuron Disease: complications / Motor
                      Neuron Disease: genetics / Motor Neuron Disease: metabolism
                      / Motor Neuron Disease: pathology / Neuroglia: metabolism /
                      Neuroglia: pathology / Neurons: metabolism / Neurons:
                      pathology / Proteins: genetics / Proteins: metabolism / Rats
                      / Spinal Cord: metabolism / Spinal Cord: pathology / Adaptor
                      Proteins, Signal Transducing (NLM Chemicals) / C9orf72
                      Protein (NLM Chemicals) / C9orf72 protein, human (NLM
                      Chemicals) / Proteins (NLM Chemicals) / UNC119 protein,
                      human (NLM Chemicals)},
      cin          = {AG Edbauer / Ext HZM / Ext LMU Klinik / AG Levin},
      ddc          = {610},
      cid          = {I:(DE-2719)1110004 / I:(DE-2719)5000050 /
                      I:(DE-2719)5000049 / I:(DE-2719)1111016},
      pnm          = {342 - Disease Mechanisms and Model Systems (POF3-342) / 344
                      - Clinical and Health Care Research (POF3-344)},
      pid          = {G:(DE-HGF)POF3-342 / G:(DE-HGF)POF3-344},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:26085200},
      pmc          = {pmc:PMC4575390},
      doi          = {10.1007/s00401-015-1450-z},
      url          = {https://pub.dzne.de/record/138124},
}