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@ARTICLE{Aly:259239,
      author       = {Aly, Amr and Laszlo, Zsofia I. and Rajkumar, Sandeep and
                      Demir, Tugba and Hindley, Nicole and Lamont, Douglas J. and
                      Lehmann, Johannes and Seidel, Mira and Sommer, Daniel and
                      Franz-Wachtel, Mirita and Barletta, Francesca and Heumos,
                      Simon and Czemmel, Stefan and Kabashi, Edor and Ludolph,
                      Albert and Böckers, Tobias and Henstridge, Christopher M.
                      and Catanese, Alberto},
      title        = {{I}ntegrative proteomics highlight presynaptic alterations
                      and c-{J}un misactivation as convergent pathomechanisms in
                      {ALS}},
      journal      = {Acta neuropathologica},
      volume       = {146},
      issn         = {0001-6322},
      address      = {Heidelberg},
      publisher    = {Springer},
      reportid     = {DZNE-2023-00740},
      pages        = {451 - 475},
      year         = {2023},
      abstract     = {Amyotrophic Lateral Sclerosis (ALS) is a fatal
                      neurodegenerative disease mainly affecting upper and lower
                      motoneurons. Several functionally heterogeneous genes have
                      been associated with the familial form of this disorder
                      (fALS), depicting an extremely complex pathogenic landscape.
                      This heterogeneity has limited the identification of an
                      effective therapy, and this bleak prognosis will only
                      improve with a greater understanding of convergent disease
                      mechanisms. Recent evidence from human post-mortem material
                      and diverse model systems has highlighted the synapse as a
                      crucial structure actively involved in disease progression,
                      suggesting that synaptic aberrations might represent a
                      shared pathological feature across the ALS spectrum. To test
                      this hypothesis, we performed the first comprehensive
                      analysis of the synaptic proteome from post-mortem spinal
                      cord and human iPSC-derived motoneurons carrying mutations
                      in the major ALS genes. This integrated approach highlighted
                      perturbations in the molecular machinery controlling vesicle
                      release as a shared pathomechanism in ALS. Mechanistically,
                      phosphoproteomic analysis linked the presynaptic vesicular
                      phenotype to an accumulation of cytotoxic protein aggregates
                      and to the pro-apoptotic activation of the transcription
                      factor c-Jun, providing detailed insights into the shared
                      pathobiochemistry in ALS. Notably, sub-chronic treatment of
                      our iPSC-derived motoneurons with the fatty acid
                      docosahexaenoic acid exerted a neuroprotective effect by
                      efficiently rescuing the alterations revealed by our
                      multidisciplinary approach. Together, this study provides
                      strong evidence for the central and convergent role played
                      by the synaptic microenvironment within the ALS spinal cord
                      and highlights a potential therapeutic target that
                      counteracts degeneration in a heterogeneous cohort of human
                      motoneuron cultures.},
      keywords     = {Humans / Amyotrophic Lateral Sclerosis: pathology /
                      Neurodegenerative Diseases: pathology / Proteomics /
                      Superoxide Dismutase-1: genetics / Motor Neurons: metabolism
                      / ALS (Other) / Motoneuron (Other) / Proteomics (Other) /
                      Spinal cord (Other) / Synapse (Other) / hiPSC (Other) /
                      Superoxide Dismutase-1 (NLM Chemicals)},
      cin          = {AG Böckers / Clinical Study Center Ulm},
      ddc          = {610},
      cid          = {I:(DE-2719)1910002 / I:(DE-2719)5000077},
      pnm          = {352 - Disease Mechanisms (POF4-352) / 353 - Clinical and
                      Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-352 / G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pmc          = {pmc:PMC10412488},
      pubmed       = {pmid:37488208},
      doi          = {10.1007/s00401-023-02611-y},
      url          = {https://pub.dzne.de/record/259239},
}