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@ARTICLE{GruijsdaSilva:163509,
      author       = {Gruijs da Silva, Lara Aletta and Simonetti, Francesca and
                      Hutten, Saskia and Riemenschneider, Henrick and Sternburg,
                      Erin L and Pietrek, Lisa M and Gebel, Jakob and Dötsch,
                      Volker and Edbauer, Dieter and Hummer, Gerhard and Stelzl,
                      Lukas S and Dormann, Dorothee},
      title        = {{D}isease-linked {TDP}-43 hyperphosphorylation suppresses
                      {TDP}-43 condensation and aggregation.},
      journal      = {The EMBO journal},
      volume       = {41},
      number       = {8},
      issn         = {1460-2075},
      address      = {Hoboken, NJ [u.a.]},
      publisher    = {Wiley},
      reportid     = {DZNE-2022-00269},
      pages        = {e108443},
      year         = {2022},
      note         = {(CC BY)},
      abstract     = {Post-translational modifications (PTMs) have emerged as key
                      modulators of protein phase separation and have been linked
                      to protein aggregation in neurodegenerative disorders. The
                      major aggregating protein in amyotrophic lateral sclerosis
                      and frontotemporal dementia, the RNA-binding protein TAR
                      DNA-binding protein (TDP-43), is hyperphosphorylated in
                      disease on several C-terminal serine residues, a process
                      generally believed to promote TDP-43 aggregation. Here, we
                      however find that Casein kinase 1δ-mediated TDP-43
                      hyperphosphorylation or C-terminal phosphomimetic mutations
                      reduce TDP-43 phase separation and aggregation, and instead
                      render TDP-43 condensates more liquid-like and dynamic.
                      Multi-scale molecular dynamics simulations reveal reduced
                      homotypic interactions of TDP-43 low-complexity domains
                      through enhanced solvation of phosphomimetic residues.
                      Cellular experiments show that phosphomimetic substitutions
                      do not affect nuclear import or RNA regulatory functions of
                      TDP-43, but suppress accumulation of TDP-43 in membrane-less
                      organelles and promote its solubility in neurons. We
                      speculate that TDP-43 hyperphosphorylation may be a
                      protective cellular response to counteract TDP-43
                      aggregation.},
      keywords     = {Amyotrophic Lateral Sclerosis: genetics / Amyotrophic
                      Lateral Sclerosis: metabolism / DNA-Binding Proteins:
                      metabolism / Frontotemporal Dementia / Humans / Protein
                      Aggregates / RNA-Binding Proteins: genetics / RNA-Binding
                      Proteins: metabolism / RNA-binding protein (Other) / TDP-43
                      (Other) / neurodegeneration (Other) / phase separation
                      (Other) / phosphorylation (Other)},
      cin          = {Ext LMU / AG Edbauer},
      ddc          = {570},
      cid          = {I:(DE-2719)5000048 / I:(DE-2719)1110004},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pmc          = {pmc:PMC9016352},
      pubmed       = {pmid:35112738},
      doi          = {10.15252/embj.2021108443},
      url          = {https://pub.dzne.de/record/163509},
}