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@ARTICLE{Nihei:141597,
      author       = {Nihei, Yoshihiro and Mori, Kohji and Werner, Georg and
                      Arzberger, Thomas and Zhou, Qihui and Khosravi, Bahram and
                      Japtok, Julia and Hermann, Andreas and Sommacal, Andreas and
                      Weber, Markus and Degeneration, German Consortium for
                      Frontotemporal Lobar and Alliance, Bavarian Brain Banking
                      and Kamp, Frits and Nuscher, Brigitte and Edbauer, Dieter
                      and Haass, Christian},
      title        = {{P}oly-glycine-alanine exacerbates {C}9orf72 repeat
                      expansion-mediated {DNA} damage via sequestration of
                      phosphorylated {ATM} and loss of nuclear hn{RNPA}3.},
      journal      = {Acta neuropathologica},
      volume       = {139},
      number       = {1},
      issn         = {0001-6322},
      address      = {Heidelberg},
      publisher    = {Springer},
      reportid     = {DZNE-2020-07921},
      pages        = {99-118},
      year         = {2020},
      abstract     = {Repeat expansion in C9orf72 causes amyotrophic lateral
                      sclerosis and frontotemporal lobar degeneration. Expanded
                      sense and antisense repeat RNA transcripts in C9orf72 are
                      translated into five dipeptide-repeat proteins (DPRs) in an
                      AUG-independent manner. We previously identified the
                      heterogeneous ribonucleoprotein (hnRNP) A3 as an interactor
                      of the sense repeat RNA that reduces its translation into
                      DPRs. Furthermore, we found that hnRNPA3 is depleted from
                      the nucleus and partially mislocalized to cytoplasmic
                      poly-GA inclusions in C9orf72 patients, suggesting that
                      poly-GA sequesters hnRNPA3 within the cytoplasm. We now
                      demonstrate that hnRNPA3 also binds to the antisense repeat
                      RNA. Both DPR production and deposition from sense and
                      antisense RNA repeats are increased upon hnRNPA3 reduction.
                      All DPRs induced DNA double strand breaks (DSB), which was
                      further enhanced upon reduction of hnRNPA3.
                      Poly-glycine-arginine and poly-proline-arginine increased
                      foci formed by phosphorylated Ataxia Telangiectasia
                      Mutated (pATM), a major sensor of DSBs, whereas
                      poly-glycine-alanine (poly-GA) evoked a reduction of pATM
                      foci. In dentate gyri of C9orf72 patients, lower nuclear
                      hnRNPA3 levels were associated with increased DNA damage.
                      Moreover, enhanced poly-GA deposition correlated with
                      reduced pATM foci. Since cytoplasmic pATM deposits partially
                      colocalized with poly-GA deposits, these results suggest
                      that poly-GA, the most frequent DPR observed in C9orf72
                      patients, differentially causes DNA damage and that poly-GA
                      selectively sequesters pATM in the cytoplasm inhibiting its
                      recruitment to sites of DNA damage. Thus, mislocalization of
                      nuclear hnRNPA3 caused by poly-GA leads to increased poly-GA
                      production, which partially depletes pATM, and consequently
                      enhances DSB.},
      keywords     = {Aged / Amyotrophic Lateral Sclerosis: genetics /
                      Amyotrophic Lateral Sclerosis: metabolism / Ataxia
                      Telangiectasia Mutated Proteins: metabolism / C9orf72
                      Protein: genetics / DNA Damage: genetics / Dinucleotide
                      Repeats: physiology / Female / Frontotemporal Lobar
                      Degeneration: genetics / Frontotemporal Lobar Degeneration:
                      metabolism / Heterogeneous-Nuclear Ribonucleoprotein Group
                      A-B: metabolism / Humans / Male / Middle Aged /
                      Phosphorylation},
      cin          = {AG Haass old / Clinical Dementia Research München / AG
                      Edbauer / AG Teipel / AG Zhou},
      ddc          = {610},
      cid          = {I:(DE-2719)1110007 / I:(DE-2719)1111016 /
                      I:(DE-2719)1110004 / I:(DE-2719)1510100 /
                      I:(DE-2719)5000080},
      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:31642962},
      pmc          = {pmc:PMC6942035},
      doi          = {10.1007/s00401-019-02082-0},
      url          = {https://pub.dzne.de/record/141597},
}