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@ARTICLE{Catanese:155693,
      author       = {Catanese, Alberto and Rajkumar, Sandeep and Sommer, Daniel
                      and Freisem, Dennis and Wirth, Alexander and Aly, Amr and
                      Massa-López, David and Olivieri, Andrea and Torelli,
                      Federica and Ioannidis, Valentin and Lipecka, Joanna and
                      Guerrera, Ida Chiara and Zytnicki, Daniel and Ludolph,
                      Albert and Kabashi, Edor and Mulaw, Medhanie A and Roselli,
                      Francesco and Böckers, Tobias},
      title        = {{S}ynaptic disruption and {CREB}-regulated transcription
                      are restored by {K}+ channel blockers in {ALS}.},
      journal      = {EMBO molecular medicine},
      volume       = {13},
      number       = {7},
      issn         = {1757-4684},
      address      = {Heidelberg},
      publisher    = {EMBO Press},
      reportid     = {DZNE-2021-00861},
      pages        = {e13131},
      year         = {2021},
      abstract     = {Amyotrophic lateral sclerosis (ALS) is a fatal
                      neurodegenerative disease, which is still missing effective
                      therapeutic strategies. Although manipulation of neuronal
                      excitability has been tested in murine and human ALS models,
                      it is still under debate whether neuronal activity might
                      represent a valid target for efficient therapies. In this
                      study, we exploited a combination of transcriptomics,
                      proteomics, optogenetics and pharmacological approaches to
                      investigate the activity-related pathological features of
                      iPSC-derived C9orf72-mutant motoneurons (MN). We found that
                      human ALSC9orf72 MN are characterized by accumulation of
                      aberrant aggresomes, reduced expression of synaptic genes,
                      loss of synaptic contacts and a dynamic 'malactivation' of
                      the transcription factor CREB. A similar phenotype was also
                      found in TBK1-mutant MN and upon overexpression of poly(GA)
                      aggregates in primary neurons, indicating a strong
                      convergence of pathological phenotypes on synaptic
                      dysregulation. Notably, these alterations, along with
                      neuronal survival, could be rescued by treating ALS-related
                      neurons with the K+ channel blockers Apamin and XE991,
                      which, respectively, target the SK and the Kv7 channels.
                      Thus, our study shows that restoring the activity-dependent
                      transcriptional programme and synaptic composition exerts a
                      neuroprotective effect on ALS disease progression.},
      keywords     = {Amyotrophic Lateral Sclerosis: drug therapy / Amyotrophic
                      Lateral Sclerosis: genetics / Animals / Humans / Induced
                      Pluripotent Stem Cells / Mice / Motor Neurons /
                      Neurodegenerative Diseases / Neuroprotective Agents / ALS
                      (Other) / CREB (Other) / hiPSC (Other) / motoneuron (Other)
                      / synapse (Other)},
      cin          = {Clinical Study Center Ulm / AG Roselli / AG Böckers},
      ddc          = {610},
      cid          = {I:(DE-2719)5000077 / I:(DE-2719)1910001 /
                      I:(DE-2719)1910002},
      pnm          = {352 - Disease Mechanisms (POF4-352) / 353 - Clinical and
                      Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-352 / G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:34125498},
      pmc          = {pmc:PMC8261490},
      doi          = {10.15252/emmm.202013131},
      url          = {https://pub.dzne.de/record/155693},
}