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@ARTICLE{Gnther:163726,
      author       = {Günther, René and Pal, Arun and Williams, Chloe and
                      Zimyanin, Vitaly L. and Liehr, Maria and von Neubeck, Cläre
                      and Krause, Mechthild and Parab, Mrudula G. and Petri,
                      Susanne and Kalmbach, Norman and Marklund, Stefan L. and
                      Sterneckert, Jared and Munch Andersen, Peter and Wegner,
                      Florian and Gilthorpe, Jonathan D. and Hermann, Andreas},
      title        = {{A}lteration of {M}itochondrial {I}ntegrity as {U}pstream
                      {E}vent in the {P}athophysiology of {SOD}1-{ALS}},
      journal      = {Cells},
      volume       = {11},
      number       = {7},
      issn         = {2073-4409},
      address      = {Basel},
      publisher    = {MDPI},
      reportid     = {DZNE-2022-00465},
      pages        = {1246},
      year         = {2022},
      abstract     = {Little is known about the early pathogenic events by which
                      mutant superoxide dismutase 1 (SOD1) causes amyotrophic
                      lateral sclerosis (ALS). This lack of mechanistic
                      understanding is a major barrier to the development and
                      evaluation of efficient therapies. Although protein
                      aggregation is known to be involved, it is not understood
                      how mutant SOD1 causes degeneration of motoneurons (MNs).
                      Previous research has relied heavily on the overexpression
                      of mutant SOD1, but the clinical relevance of SOD1
                      overexpression models remains questionable. We used a human
                      induced pluripotent stem cell (iPSC) model of spinal MNs and
                      three different endogenous ALS-associated SOD1 mutations
                      (D90Ahom, R115Ghet or A4Vhet) to investigate early cellular
                      disturbances in MNs. Although enhanced misfolding and
                      aggregation of SOD1 was induced by proteasome inhibition, it
                      was not affected by activation of the stress granule
                      pathway. Interestingly, we identified loss of mitochondrial,
                      but not lysosomal, integrity as the earliest common
                      pathological phenotype, which preceded elevated levels of
                      insoluble, aggregated SOD1. A super-elongated mitochondrial
                      morphology with impaired inner mitochondrial membrane
                      potential was a unifying feature in mutant SOD1 iPSC-derived
                      MNs. Impaired mitochondrial integrity was most prominent in
                      mutant D90Ahom MNs, whereas both soluble disordered and
                      detergent-resistant misfolded SOD1 was more prominent in
                      R115Ghet and A4Vhet mutant lines. Taking advantage of
                      patient-specific models of SOD1-ALS in vitro, our data
                      suggest that mitochondrial dysfunction is one of the first
                      crucial steps in the pathogenic cascade that leads to
                      SOD1-ALS and also highlights the need for individualized
                      medical approaches for SOD1-ALS.},
      keywords     = {Amyotrophic Lateral Sclerosis: metabolism / Humans /
                      Induced Pluripotent Stem Cells: metabolism / Mitochondria:
                      metabolism / Superoxide Dismutase-1: genetics / Superoxide
                      Dismutase-1: metabolism},
      cin          = {Clinical Study Team Dresden ; AG Falkenburger / AG Teipel},
      ddc          = {570},
      cid          = {I:(DE-2719)1710012 / I:(DE-2719)1510100},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pmc          = {pmc:PMC8997900},
      pubmed       = {pmid:35406813},
      doi          = {10.3390/cells11071246},
      url          = {https://pub.dzne.de/record/163726},
}