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@ARTICLE{GarciaMorato:163198,
      author       = {Garcia Morato, Jorge and Hans, Friederike and von Zweydorf,
                      Felix and Feederle, Regina and Elsässer, Simon J and
                      Skodras, Angelos and Gloeckner, Christian Johannes and
                      Buratti, Emanuele and Neumann, Manuela and Kahle, Philipp},
      title        = {{S}irtuin-1 sensitive lysine-136 acetylation drives phase
                      separation and pathological aggregation of {TDP}-43.},
      journal      = {Nature Communications},
      volume       = {13},
      number       = {1},
      issn         = {2041-1723},
      address      = {[London]},
      publisher    = {Nature Publishing Group UK},
      reportid     = {DZNE-2022-00033},
      pages        = {1223},
      year         = {2022},
      abstract     = {Trans-activation response DNA-binding protein of 43 kDa
                      (TDP-43) regulates RNA processing and forms
                      neuropathological aggregates in patients with amyotrophic
                      lateral sclerosis and frontotemporal lobar degeneration.
                      Investigating TDP-43 post-translational modifications, we
                      discovered that K84 acetylation reduced nuclear import
                      whereas K136 acetylation impaired RNA binding and splicing
                      capabilities of TDP-43. Such failure of RNA interaction
                      triggered TDP-43 phase separation mediated by the C-terminal
                      low complexity domain, leading to the formation of insoluble
                      aggregates with pathologically phosphorylated and
                      ubiquitinated TDP-43. Introduction of acetyl-lysine at the
                      identified sites via amber suppression confirmed the results
                      from site-directed mutagenesis. K84-acetylated TDP-43 showed
                      cytoplasmic mislocalization, and the aggregation propensity
                      of K136-acetylated TDP-43 was confirmed. We generated
                      antibodies selective for TDP-43 acetylated at these lysines,
                      and found that sirtuin-1 can potently deacetylate
                      K136-acetylated TDP-43 and reduce its aggregation
                      propensity. Thus, distinct lysine acetylations modulate
                      nuclear import, RNA binding and phase separation of TDP-43,
                      suggesting regulatory mechanisms for TDP-43 pathogenesis.},
      keywords     = {Acetylation / Amyotrophic Lateral Sclerosis: metabolism /
                      DNA-Binding Proteins: metabolism / Humans / Lysine:
                      metabolism / Protein Aggregation, Pathological: metabolism /
                      Protein Processing, Post-Translational / RNA: metabolism /
                      Sirtuin 1: genetics / Sirtuin 1: metabolism},
      cin          = {AG Gasser 1 / AG Kahle 2 / AG Gloeckner 2 / AG Feederle /
                      AG Jucker / AG Neumann},
      ddc          = {500},
      cid          = {I:(DE-2719)1210000 / I:(DE-2719)1210000-4 /
                      I:(DE-2719)1210007 / I:(DE-2719)1140004 / I:(DE-2719)1210001
                      / I:(DE-2719)1210003},
      pnm          = {353 - Clinical and Health Care Research (POF4-353) / 352 -
                      Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-353 / G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pmc          = {pmc:PMC8907366},
      pubmed       = {pmid:35264561},
      doi          = {10.1038/s41467-022-28822-7},
      url          = {https://pub.dzne.de/record/163198},
}