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@ARTICLE{NakosBimpos:270308,
      author       = {Nakos Bimpos, Modestos and Karali, Katerina and Antoniou,
                      Christine and Palermos, Dionysios and Fouka, Maria and
                      Delis, Anastasios and Tzieras, Iason and Chrousos, George
                      Panagiotis and Koutmani, Yassemi and Stefanis, Leonidas and
                      Polissidis, Alexia},
      title        = {{A}lpha-synuclein-induced stress sensitivity renders the
                      {P}arkinson's disease brain susceptible to
                      neurodegeneration.},
      journal      = {Acta Neuropathologica Communications},
      volume       = {12},
      number       = {1},
      issn         = {2051-5960},
      address      = {London},
      publisher    = {Biomed Central},
      reportid     = {DZNE-2024-00780},
      pages        = {100},
      year         = {2024},
      abstract     = {A link between chronic stress and Parkinson's disease (PD)
                      pathogenesis is emerging. Ample evidence demonstrates that
                      the presynaptic neuronal protein alpha-synuclein (asyn) is
                      closely tied to PD pathogenesis. However, it is not known
                      whether stress system dysfunction is present in PD, if asyn
                      is involved, and if, together, they contribute to
                      neurodegeneration. To address these questions, we assess
                      stress axis function in transgenic rats overexpressing
                      full-length wildtype human asyn (asyn BAC rats) and perform
                      multi-level stress and PD phenotyping following chronic
                      corticosterone administration. Stress signaling, namely
                      corticotropin-releasing factor, glucocorticoid and
                      mineralocorticoid receptor gene expression, is also examined
                      in post-mortem PD patient brains. Overexpression of human
                      wildtype asyn leads to HPA axis dysregulation in rats, while
                      chronic corticosterone administration significantly
                      aggravates nigrostriatal degeneration, serine129
                      phosphorylated asyn (pS129) expression and
                      neuroinflammation, leading to phenoconversion from a
                      prodromal to an overt motor PD phenotype. Interestingly,
                      chronic corticosterone in asyn BAC rats induces a robust,
                      twofold increase in pS129 expression in the hypothalamus,
                      the master regulator of the stress response, while the
                      hippocampus, both a regulator and a target of the stress
                      response, also demonstrates elevated pS129 asyn levels and
                      altered markers of stress signalling. Finally, defective
                      hippocampal stress signalling is mirrored in human PD brains
                      and correlates with asyn expression levels. Taken together,
                      our results link brain stress system dysregulation with asyn
                      and provide evidence that elevated circulating
                      glucocorticoids can contribute to asyn-induced
                      neurodegeneration, ultimately triggering phenoconversion
                      from prodromal to overt PD.},
      keywords     = {alpha-Synuclein: metabolism / alpha-Synuclein: genetics /
                      Animals / Parkinson Disease: metabolism / Parkinson Disease:
                      pathology / Humans / Rats, Transgenic / Rats / Stress,
                      Psychological: metabolism / Stress, Psychological: pathology
                      / Male / Corticosterone: blood / Brain: metabolism / Brain:
                      pathology / Hypothalamo-Hypophyseal System: metabolism /
                      Female / Pituitary-Adrenal System: metabolism /
                      Parkinson’s disease (Other) / Alpha-synuclein (Other) /
                      Chronic stress (Other) / Corticosterone (Other) /
                      Glucocorticoids (Other) / HPA axis (Other) / Parkinson’s
                      disease (Other) / alpha-Synuclein (NLM Chemicals) /
                      Corticosterone (NLM Chemicals) / SNCA protein, human (NLM
                      Chemicals)},
      cin          = {AG Garthe},
      ddc          = {610},
      cid          = {I:(DE-2719)1740001},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pmc          = {pmc:PMC11181569},
      pubmed       = {pmid:38886854},
      doi          = {10.1186/s40478-024-01797-w},
      url          = {https://pub.dzne.de/record/270308},
}