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@ARTICLE{CaldiGomes:270146,
      author       = {Caldi Gomes, Lucas and Hänzelmann, Sonja and Hausmann,
                      Fabian and Khatri, Robin and Oller, Sergio and Parvaz, Mojan
                      and Tzeplaeff, Laura and Pasetto, Laura and Gebelin, Marie
                      and Ebbing, Melanie and Holzapfel, Constantin and Columbro,
                      Stefano Fabrizio and Scozzari, Serena and Knöferle, Johanna
                      and Cordts, Isabell and Demleitner, Antonia F and Deschauer,
                      Marcus and Dufke, Claudia and Sturm, Marc and Zhou, Qihui
                      and Zelina, Pavol and Sudria-Lopez, Emma and Haack, Tobias B
                      and Streb, Sebastian and Kuzma-Kozakiewicz, Magdalena and
                      Edbauer, Dieter and Pasterkamp, R Jeroen and Laczko, Endre
                      and Rehrauer, Hubert and Schlapbach, Ralph and Carapito,
                      Christine and Bonetto, Valentina and Bonn, Stefan and
                      Lingor, Paul},
      title        = {{M}ultiomic {ALS} signatures highlight subclusters and sex
                      differences suggesting the {MAPK} pathway as therapeutic
                      target.},
      journal      = {Nature Communications},
      volume       = {15},
      number       = {1},
      issn         = {2041-1723},
      address      = {[London]},
      publisher    = {Nature Publishing Group UK},
      reportid     = {DZNE-2024-00744},
      pages        = {4893},
      year         = {2024},
      abstract     = {Amyotrophic lateral sclerosis (ALS) is a debilitating motor
                      neuron disease and lacks effective disease-modifying
                      treatments. This study utilizes a comprehensive multiomic
                      approach to investigate the early and sex-specific molecular
                      mechanisms underlying ALS. By analyzing the prefrontal
                      cortex of 51 patients with sporadic ALS and 50 control
                      subjects, alongside four transgenic mouse models (C9orf72-,
                      SOD1-, TDP-43-, and FUS-ALS), we have uncovered significant
                      molecular alterations associated with the disease. Here, we
                      show that males exhibit more pronounced changes in molecular
                      pathways compared to females. Our integrated analysis of
                      transcriptomes, (phospho)proteomes, and miRNAomes also
                      identified distinct ALS subclusters in humans, characterized
                      by variations in immune response, extracellular matrix
                      composition, mitochondrial function, and RNA processing. The
                      molecular signatures of human subclusters were reflected in
                      specific mouse models. Our study highlighted the
                      mitogen-activated protein kinase (MAPK) pathway as an early
                      disease mechanism. We further demonstrate that trametinib, a
                      MAPK inhibitor, has potential therapeutic benefits in vitro
                      and in vivo, particularly in females, suggesting a direction
                      for developing targeted ALS treatments.},
      keywords     = {Amyotrophic Lateral Sclerosis: genetics / Amyotrophic
                      Lateral Sclerosis: drug therapy / Amyotrophic Lateral
                      Sclerosis: metabolism / Humans / Female / Animals / Male /
                      Mice / Mice, Transgenic / MAP Kinase Signaling System: drug
                      effects / Disease Models, Animal / Pyridones: pharmacology /
                      Pyridones: therapeutic use / RNA-Binding Protein FUS:
                      metabolism / RNA-Binding Protein FUS: genetics / Prefrontal
                      Cortex: metabolism / Transcriptome / Superoxide Dismutase-1:
                      genetics / Superoxide Dismutase-1: metabolism / DNA-Binding
                      Proteins: metabolism / DNA-Binding Proteins: genetics /
                      Middle Aged / MicroRNAs: genetics / MicroRNAs: metabolism /
                      C9orf72 Protein: genetics / C9orf72 Protein: metabolism /
                      Sex Characteristics / Aged / Sex Factors / Pyrimidinones /
                      trametinib (NLM Chemicals) / Pyridones (NLM Chemicals) /
                      RNA-Binding Protein FUS (NLM Chemicals) / Superoxide
                      Dismutase-1 (NLM Chemicals) / DNA-Binding Proteins (NLM
                      Chemicals) / MicroRNAs (NLM Chemicals) / C9orf72 Protein
                      (NLM Chemicals) / TARDBP protein, human (NLM Chemicals) /
                      SOD1 protein, human (NLM Chemicals) / FUS protein, human
                      (NLM Chemicals) / Pyrimidinones (NLM Chemicals)},
      cin          = {Clinical Research (Munich) / AG Zhou / AG Edbauer},
      ddc          = {500},
      cid          = {I:(DE-2719)1111015 / I:(DE-2719)5000080 /
                      I:(DE-2719)1110004},
      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},
      pubmed       = {pmid:38849340},
      pmc          = {pmc:PMC11161513},
      doi          = {10.1038/s41467-024-49196-y},
      url          = {https://pub.dzne.de/record/270146},
}