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@ARTICLE{Grozdanov:155805,
      author       = {Grozdanov, Veselin and Bousset, Luc and Hoffmeister, Meike
                      and Bliederhaeuser, Corinna and Meier, Christoph and
                      Madiona, Karine and Pieri, Laura and Kiechle, Martin and
                      McLean, Pamela J and Kassubek, Jan and Behrends, Christian
                      and Ludolph, Albert and Weishaupt, Jochen H and Melki,
                      Ronald and Danzer, Karin M},
      title        = {{I}ncreased {I}mmune {A}ctivation by {P}athologic
                      α-{S}ynuclein in {P}arkinson's {D}isease.},
      journal      = {Annals of neurology},
      volume       = {86},
      number       = {4},
      issn         = {1531-8249},
      address      = {Hoboken, NJ},
      publisher    = {Wiley-Blackwell},
      reportid     = {DZNE-2021-00965},
      pages        = {593 - 606},
      year         = {2019},
      abstract     = {Excessive inflammation in the central nervous system (CNS)
                      and the periphery can result in neurodegeneration and
                      parkinsonism. Recent evidence suggests that immune responses
                      in Parkinson disease patients are dysregulated, leading to
                      an increased inflammatory reaction to unspecific triggers.
                      Although α-synuclein pathology is the hallmark of Parkinson
                      disease, it has not been investigated whether pathologic
                      α-synuclein is a specific trigger for excessive
                      inflammatory responses in Parkinson disease.We investigated
                      the immune response of primary human monocytes and a
                      microglial cell line to pathologic forms of α-synuclein by
                      assessing cytokine release upon exposure.We show that
                      pathologic α-synuclein (mutations, aggregation) results in
                      a robust inflammatory activation of human monocytes and
                      microglial BV2 cells. The activation is conformation-
                      dependent, with increasing fibrillation and early onset
                      mutations having the strongest effect on immune activation.
                      We also found that activation of immune cells by
                      extracellular α-synuclein is potentiated by extracellular
                      vesicles, possibly by facilitating the uptake of
                      α-synuclein. Blood extracellular vesicles from Parkinson
                      disease patients induce a stronger activation of monocytes
                      than blood extracellular vesicles from healthy controls.
                      Most importantly, monocytes from Parkinson disease patients
                      are dysregulated and hyperactive in response to stimulation
                      with pathologic α-synuclein. Furthermore, we demonstrate
                      that α-synuclein pathology in the CNS is sufficient to
                      induce the monocyte dysregulation in the periphery of a
                      mouse model.Taken together, our data suggest that
                      α-synuclein pathology and dysregulation of monocytes in
                      Parkinson disease can act together to induce excessive
                      inflammatory responses to α-synuclein. ANN NEUROL
                      2019;86:593-606.},
      keywords     = {Animals / Cells, Cultured / Cytokines: metabolism /
                      Extracellular Vesicles: immunology / Humans / Inflammation:
                      complications / Inflammation: metabolism / Mice / Mice,
                      Transgenic / Microglia: metabolism / Monocytes: metabolism /
                      Mutation / Parkinson Disease: immunology / Parkinson
                      Disease: metabolism / alpha-Synuclein: adverse effects /
                      alpha-Synuclein: genetics / Cytokines (NLM Chemicals) /
                      alpha-Synuclein (NLM Chemicals)},
      ddc          = {610},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:31343083},
      doi          = {10.1002/ana.25557},
      url          = {https://pub.dzne.de/record/155805},
}