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@ARTICLE{VanDenBerge:872758,
      author       = {Van Den Berge, Nathalie and Ferreira, Nelson and Gram,
                      Hjalte and Mikkelsen, Trine Werenberg and Alstrup, Aage
                      Kristian Olsen and Casadei, Nicolas and Tsung-Pin, Pai and
                      Riess, Olaf and Nyengaard, Jens Randel and Tamgüney,
                      Gültekin and Jensen, Poul Henning and Borghammer, Per},
      title        = {{E}vidence for bidirectional and trans-synaptic
                      parasympathetic and sympathetic propagation of
                      alpha-synuclein in rats},
      journal      = {Acta neuropathologica},
      volume       = {138},
      number       = {4},
      issn         = {1432-0533},
      address      = {Heidelberg},
      publisher    = {Springer},
      reportid     = {FZJ-2020-00236},
      pages        = {535 - 550},
      year         = {2019},
      abstract     = {The conversion of endogenous alpha-synuclein (asyn) to
                      pathological asyn-enriched aggregates is a hallmark of
                      Parkinson’s disease (PD). These inclusions can be detected
                      in the central and enteric nervous system (ENS). Moreover,
                      gastrointestinal symptoms can appear up to 20 years before
                      the diagnosis of PD. The dual-hit hypothesis posits that
                      pathological asyn aggre-gation starts in the ENS, and
                      retrogradely spreads to the brain. In this study, we tested
                      this hypothesis by directly injecting preformed asyn fibrils
                      into the duodenum wall of wild-type rats and transgenic rats
                      with excess levels of human asyn. We provide a meticulous
                      characterization of the bacterial artificial chromosome
                      (BAC) transgenic rat model with respect to ini-tial
                      propagation of pathological asyn along the parasympathetic
                      and sympathetic pathways to the brainstem, by performing
                      immunohistochemistry at early time points post-injection.
                      Induced pathology was observed in all key structures along
                      the sympathetic and parasympathetic pathways (ENS, autonomic
                      ganglia, intermediolateral nucleus of the spinal cord (IML),
                      heart, dorsal motor nucleus of the vagus, and locus
                      coeruleus (LC)) and persisted for at least 4 months
                      post-injection. In contrast, asyn propagation was not
                      detected in wild-type rats, nor in vehicle-injected BAC
                      rats. The presence of pathology in the IML, LC, and heart
                      indicate trans-synaptic spread of the pathology.
                      Additionally, the observed asyn inclusions in the stomach
                      and heart may indicate secondary anterograde propagation
                      after initial retrograde spreading. In summary,
                      trans-synaptic propagation of asyn in the BAC rat model is
                      fully compatible with the “body-first hypothesis” of PD
                      etiopatho-genesis. To our knowledge, this is the first
                      animal model evidence of asyn propagation to the heart, and
                      the first indication of bidirectional asyn propagation via
                      the vagus nerve, i.e., duodenum-to-brainstem-to-stomach. The
                      BAC rat model could be very valuable for detailed
                      mechanistic studies of the dual-hit hypothesis, and for
                      studies of disease modifying therapies targeting early
                      pathology in the gastrointestinal tract.},
      cin          = {ICS-6},
      ddc          = {610},
      cid          = {I:(DE-Juel1)ICS-6-20110106},
      pnm          = {553 - Physical Basis of Diseases (POF3-553)},
      pid          = {G:(DE-HGF)POF3-553},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:31254094},
      UT           = {WOS:000488931000004},
      doi          = {10.1007/s00401-019-02040-w},
      url          = {https://juser.fz-juelich.de/record/872758},
}