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@ARTICLE{Abdeen:633348,
      author       = {Abdeen, Amr H. and Trist, Benjamin G. and Nikseresht, Sara
                      and Harwood, Richard and Roudeau, Stéphane and Rowlands,
                      Benjamin D. and Kreilaus, Fabian and Cottam, Veronica and
                      Mor, David and Richardson, Miriam and Siciliano, Joel and
                      Forkgen, Julia and Schaffer, Greta and Genoud, Sian and Li,
                      Anne A. and Proschogo, Nicholas and Antonio, Bernadeth and
                      Falkenberg, Gerald and Brueckner, Dennis and Kysenius, Kai
                      and Liddell, Jeffrey R. and Fat, Sandrine Chan Moi and Wu,
                      Sharlynn and Fifita, Jennifer and Lockwood, Thomas E. and
                      Bishop, David P. and Blair, Ian and Ortega, Richard and
                      Crouch, Peter J. and Double, Kay},
      title        = {{P}arkinson-like wild-type superoxide dismutase 1 pathology
                      induces nigral dopamine neuron degeneration in a novel
                      murine model},
      journal      = {Acta neuropathologica},
      volume       = {149},
      number       = {1},
      issn         = {0001-6322},
      address      = {Heidelberg},
      publisher    = {Springer},
      reportid     = {PUBDB-2025-02394},
      pages        = {22},
      year         = {2025},
      abstract     = {Atypical wild-type superoxide dismutase 1 (SOD1) protein
                      misfolding and deposition occurs specifically within the
                      degenerating substantia nigra pars compacta (SNc) in
                      Parkinson disease. Mechanisms driving the formation of this
                      pathology and relationship with SNc dopamine neuron health
                      are yet to be fully understood. We applied proteomic mass
                      spectrometry and synchrotron-based biometal quantification
                      to post-mortem brain tissues from the SNc of Parkinson
                      disease patients and age-matched controls to uncover key
                      factors underlying the formation of wild-type SOD1 pathology
                      in this disorder. We also engineered two of these factors -
                      brain copper deficiency and upregulated SOD1 protein levels
                      - into a novel mouse strain, termed the SOCK mouse, to
                      verify their involvement in the development of
                      Parkinson-like wild-type SOD1 pathology and their impact on
                      dopamine neuron health. Soluble SOD1 protein in the
                      degenerating Parkinson disease SNc exhibited altered
                      post-translational modifications, which may underlie changes
                      to the enzymatic activity and aggregation of the protein in
                      this region. These include decreased copper binding,
                      dysregulation of physiological glycosylation, and atypical
                      oxidation and glycation of key SOD1 amino acid residues. We
                      demonstrated that the biochemical profile introduced in SOCK
                      mice promotes the same post-translational modifications and
                      the development of Parkinson-like wild-type SOD1 pathology
                      in the midbrain and cortex. This pathology accumulates
                      progressively with age and is accompanied by nigrostriatal
                      degeneration and dysfunction, which occur in the absence of
                      α-synuclein deposition. These mice do not exhibit weight
                      loss nor spinal cord motor neuron degeneration,
                      distinguishing them from transgenic mutant SOD1 mouse
                      models. This study provides the first in vivo evidence that
                      mismetallation and altered post-translational modifications
                      precipitates wild-type SOD1 misfolding, dysfunction, and
                      deposition in the Parkinson disease brain, which may
                      contribute to SNc dopamine neuron degeneration. Our data
                      position this pathology as a novel drug target for this
                      disorder, with a particular focus on therapies capable of
                      correcting alterations to SOD1 post-translational
                      modifications.},
      cin          = {DOOR ; HAS-User / FS-PET-S},
      ddc          = {610},
      cid          = {I:(DE-H253)HAS-User-20120731 /
                      I:(DE-H253)FS-PET-S-20190712},
      pnm          = {633 - Life Sciences – Building Blocks of Life: Structure
                      and Function (POF4-633) / 6G3 - PETRA III (DESY) (POF4-6G3)
                      / FS-Proposal: I-20230761 EC (I-20230761-EC)},
      pid          = {G:(DE-HGF)POF4-633 / G:(DE-HGF)POF4-6G3 /
                      G:(DE-H253)I-20230761-EC},
      experiment   = {EXP:(DE-H253)P-P06-20150101},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40042537},
      doi          = {10.1007/s00401-025-02859-6},
      url          = {https://bib-pubdb1.desy.de/record/633348},
}