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@ARTICLE{Dash:165289,
      author       = {Dash, Banaja and Freischmidt, Axel and Weishaupt, Jochen H
                      and Hermann, Andreas},
      title        = {{D}ownstream {E}ffects of {M}utations in {SOD}1 and
                      {TARDBP} {C}onverge on {G}ene {E}xpression {I}mpairment in
                      {P}atient-{D}erived {M}otor {N}eurons.},
      journal      = {International journal of molecular sciences},
      volume       = {23},
      number       = {17},
      issn         = {1422-0067},
      address      = {Basel},
      publisher    = {Molecular Diversity Preservation International},
      reportid     = {DZNE-2022-01582},
      pages        = {9652},
      year         = {2022},
      note         = {CC BY: https://creativecommons.org/licenses/by/4.0/},
      abstract     = {Amyotrophic Lateral Sclerosis (ALS) is a progressive and
                      fatal neurodegenerative disease marked by death of motor
                      neurons (MNs) present in the spinal cord, brain stem and
                      motor cortex. Despite extensive research, the reason for
                      neurodegeneration is still not understood. To generate novel
                      hypotheses of putative underlying molecular mechanisms, we
                      used human induced pluripotent stem cell (hiPSCs)-derived
                      motor neurons (MNs) from SOD1- and TARDBP (TDP-43
                      protein)-mutant-ALS patients and healthy controls to perform
                      high-throughput RNA-sequencing (RNA-Seq). An integrated
                      bioinformatics approach was employed to identify
                      differentially expressed genes (DEGs) and key pathways
                      underlying these familial forms of the disease (fALS). In
                      TDP43-ALS, we found dysregulation of transcripts encoding
                      components of the transcriptional machinery and transcripts
                      involved in splicing regulation were particularly affected.
                      In contrast, less is known about the role of SOD1 in RNA
                      metabolism in motor neurons. Here, we found that many
                      transcripts relevant for mitochondrial function were
                      specifically altered in SOD1-ALS, indicating that
                      transcriptional signatures and expression patterns can vary
                      significantly depending on the causal gene that is mutated.
                      Surprisingly, however, we identified a clear downregulation
                      of genes involved in protein translation in SOD1-ALS
                      suggesting that ALS-causing SOD1 mutations shift cellular
                      RNA abundance profiles to cause neural dysfunction.
                      Altogether, we provided here an extensive profiling of mRNA
                      expression in two ALS models at the cellular level,
                      corroborating the major role of RNA metabolism and gene
                      expression as a common pathomechanism in ALS.},
      keywords     = {Amyotrophic Lateral Sclerosis: genetics / DNA-Binding
                      Proteins: genetics / DNA-Binding Proteins: metabolism / Gene
                      Expression / Humans / Induced Pluripotent Stem Cells:
                      metabolism / Motor Neurons: metabolism / Mutation /
                      Neurodegenerative Diseases: metabolism / RNA: metabolism /
                      Superoxide Dismutase-1: genetics / RNA sequencing (RNA-Seq)
                      (Other) / amyotrophic lateral sclerosis (ALS) (Other) /
                      differentially expressed genes (DEG) (Other) / human induced
                      pluripotent stem cells (iPSC) (Other) / motor neurons (MN)
                      (Other) / protein-protein interaction (PPI) (Other) /
                      DNA-Binding Proteins (NLM Chemicals) / SOD1 protein, human
                      (NLM Chemicals) / TARDBP protein, human (NLM Chemicals) /
                      RNA (NLM Chemicals) / Superoxide Dismutase-1 (NLM
                      Chemicals)},
      cin          = {AG Hermann},
      ddc          = {540},
      cid          = {I:(DE-2719)1511100},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:36077049},
      pmc          = {pmc:PMC9456253},
      doi          = {10.3390/ijms23179652},
      url          = {https://pub.dzne.de/record/165289},
}