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@ARTICLE{Czuppa:164645,
      author       = {Czuppa, Mareike and Dhingra, Ashutosh and Zhou, Qihui and
                      Schludi, Carina and Koenig, Laura and Scharf, Elisabeth and
                      Farny, Daniel and Dalmia, Anupriya and Täger, Joachim and
                      Castillo Lizardo, Melissa Gissel and Katona, Eszter and
                      Mori, Kohji and Aumer, Tina and Schelter, Florian and
                      Müller, Markus and Carell, Thomas and Kalliokoski, Tuomo
                      and Messinger, Josef and Rizzu, Patrizia and Heutink, Peter
                      and Edbauer, Dieter},
      title        = {{D}rug screen in i{PSC}-{N}eurons identifies nucleoside
                      analogs as inhibitors of ({G}4{C}2)n expression in {C}9orf72
                      {ALS}/{FTD}},
      journal      = {Cell reports},
      volume       = {39},
      number       = {10},
      issn         = {2211-1247},
      address      = {[New York, NY]},
      publisher    = {Elsevier},
      reportid     = {DZNE-2022-01175},
      pages        = {110913},
      year         = {2022},
      note         = {(CC BY-NC-ND)},
      abstract     = {An intronic (G4C2)n expansion in C9orf72 causes amyotrophic
                      lateral sclerosis and frontotemporal dementia primarily
                      through gain-of-function mechanisms: the accumulation of
                      sense and antisense repeat RNA foci and dipeptide repeat
                      (DPR) proteins (poly-GA/GP/GR/PA/PR) translated from repeat
                      RNA. To therapeutically block this pathway, we screen a
                      library of 1,430 approved drugs and known bioactive
                      compounds in patient-derived induced pluripotent stem
                      cell-derived neurons (iPSC-Neurons) for inhibitors of DPR
                      expression. The clinically used guanosine/cytidine analogs
                      decitabine, entecavir, and nelarabine reduce poly-GA/GP
                      expression, with decitabine being the most potent. Hit
                      compounds nearly abolish sense and antisense RNA foci and
                      reduce expression of the repeat-containing nascent C9orf72
                      RNA transcript and its mature mRNA with minimal effects on
                      global gene expression, suggesting that they specifically
                      act on repeat transcription. Importantly, decitabine
                      treatment reduces (G4C2)n foci and DPRs in C9orf72 BAC
                      transgenic mice. Our findings suggest that nucleoside
                      analogs are a promising compound class for therapeutic
                      development in C9orf72 repeat-expansion-associated
                      disorders.},
      keywords     = {Amyotrophic Lateral Sclerosis: drug therapy / Amyotrophic
                      Lateral Sclerosis: genetics / Amyotrophic Lateral Sclerosis:
                      metabolism / Animals / C9orf72 Protein: genetics / C9orf72
                      Protein: metabolism / DNA Repeat Expansion / Decitabine:
                      metabolism / Dipeptides: metabolism / Frontotemporal
                      Dementia: genetics / Humans / Induced Pluripotent Stem
                      Cells: metabolism / Mice / Neurons: metabolism /
                      Nucleosides: metabolism / RNA, Antisense: metabolism},
      cin          = {AG Edbauer / AG Heutink 1 / München common / AG Rizzu / AG
                      Zhou},
      ddc          = {610},
      cid          = {I:(DE-2719)1110004 / I:(DE-2719)1210002 /
                      I:(DE-2719)6000016 / I:(DE-2719)1210009 /
                      I:(DE-2719)5000080},
      pnm          = {352 - Disease Mechanisms (POF4-352) / 354 - Disease
                      Prevention and Healthy Aging (POF4-354)},
      pid          = {G:(DE-HGF)POF4-352 / G:(DE-HGF)POF4-354},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:35675776},
      doi          = {10.1016/j.celrep.2022.110913},
      url          = {https://pub.dzne.de/record/164645},
}