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@ARTICLE{Khosravi:139127,
      author       = {Khosravi, Bahram and Hartmann, Hannelore and May, Stephanie
                      and Möhl, Christoph and Ederle, Helena and Michaelsen,
                      Meike and Schludi, Martin H and Dormann, Dorothee and
                      Edbauer, Dieter},
      title        = {{C}ytoplasmic poly-{GA} aggregates impair nuclear import of
                      {TDP}-43 in {C}9orf72 {ALS}/{FTLD}.},
      journal      = {Human molecular genetics},
      volume       = {26},
      number       = {4},
      issn         = {0964-6906},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {DZNE-2020-05449},
      pages        = {ddw432},
      year         = {2017},
      abstract     = {A repeat expansion in the non-coding region of C9orf72 gene
                      is the most common mutation causing frontotemporal lobar
                      degeneration (FTLD) and amyotrophic lateral sclerosis (ALS).
                      Sense and antisense transcripts are translated into
                      aggregating dipeptide repeat (DPR) proteins in all reading
                      frames (poly-GA,-GP,-GR,-PA and -PR) through an
                      unconventional mechanism. How these changes contribute to
                      cytoplasmic mislocalization and aggregation of TDP-43 and
                      thereby ultimately leading to neuron loss remains unclear.
                      The repeat RNA itself and poly-GR/PR have been linked to
                      impaired nucleocytoplasmic transport. Here, we show that
                      compact cytoplasmic poly-GA aggregates impair nuclear import
                      of a reporter containing the TDP-43 nuclear localization
                      (NLS) signal. However, a reporter containing a non-classical
                      PY-NLS was not affected. Moreover, poly-GA expression
                      prevents TNFα induced nuclear translocation of p65
                      suggesting that poly-GA predominantly impairs the
                      importin-α/β-dependent pathway. In neurons, prolonged
                      poly-GA expression induces partial mislocalization of TDP-43
                      into cytoplasmic granules. Rerouting poly-GA to the nucleus
                      prevented TDP-43 mislocalization, suggesting a cytoplasmic
                      mechanism. In rescue experiments, expression of importin-α
                      (KPNA3, KPNA4) or nucleoporins (NUP54, NUP62) restores the
                      nuclear localization of the TDP reporter. Taken together,
                      inhibition of nuclear import of TDP-43 by cytoplasmic
                      poly-GA inclusions causally links the two main aggregating
                      proteins in C9orf72 ALS/FTLD pathogenesis.},
      keywords     = {Amyotrophic Lateral Sclerosis: genetics / Amyotrophic
                      Lateral Sclerosis: metabolism / Amyotrophic Lateral
                      Sclerosis: pathology / Animals / C9orf72 Protein / DNA
                      Repeat Expansion / DNA-Binding Proteins: genetics /
                      DNA-Binding Proteins: metabolism / Frontotemporal Lobar
                      Degeneration: genetics / Frontotemporal Lobar Degeneration:
                      metabolism / Frontotemporal Lobar Degeneration: pathology /
                      Humans / Inclusion Bodies: genetics / Inclusion Bodies:
                      metabolism / Membrane Glycoproteins: genetics / Membrane
                      Glycoproteins: metabolism / Neurons: metabolism / Nuclear
                      Localization Signals: genetics / Nuclear Localization
                      Signals: metabolism / Nuclear Pore Complex Proteins:
                      genetics / Nuclear Pore Complex Proteins: metabolism /
                      Proteins: genetics / Proteins: metabolism / Rats / Tumor
                      Necrosis Factor-alpha: genetics / Tumor Necrosis
                      Factor-alpha: metabolism / alpha Karyopherins: genetics /
                      alpha Karyopherins: metabolism / C9orf72 Protein (NLM
                      Chemicals) / C9orf72 protein, human (NLM Chemicals) /
                      DNA-Binding Proteins (NLM Chemicals) / KPNA3 protein, human
                      (NLM Chemicals) / KPNA4 protein, human (NLM Chemicals) /
                      Membrane Glycoproteins (NLM Chemicals) / Nuclear
                      Localization Signals (NLM Chemicals) / Nuclear Pore Complex
                      Proteins (NLM Chemicals) / Proteins (NLM Chemicals) / TDP-43
                      protein, human (NLM Chemicals) / Tumor Necrosis Factor-alpha
                      (NLM Chemicals) / alpha Karyopherins (NLM Chemicals) /
                      nuclear pore protein p62 (NLM Chemicals)},
      cin          = {AG Edbauer / IDAF},
      ddc          = {570},
      cid          = {I:(DE-2719)1110004 / I:(DE-2719)1040200},
      pnm          = {342 - Disease Mechanisms and Model Systems (POF3-342)},
      pid          = {G:(DE-HGF)POF3-342},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:28040728},
      pmc          = {pmc:PMC5409121},
      doi          = {10.1093/hmg/ddw432},
      url          = {https://pub.dzne.de/record/139127},
}