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@ARTICLE{VanDenBerge:904320,
      author       = {Van Den Berge, Nathalie and Ferreira, Nelson and Mikkelsen,
                      Trine Werenberg and Alstrup, Aage Kristian Olsen and
                      Tamgüney, Gültekin and Karlsson, Páll and Terkelsen,
                      Astrid Juhl and Nyengaard, Jens Randel and Jensen, Poul
                      Henning and Borghammer, Per},
      title        = {{A}geing promotes pathological alpha-synuclein propagation
                      and autonomic dysfunction in wild-type rats},
      journal      = {Brain},
      volume       = {144},
      number       = {6},
      issn         = {0006-8950},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {FZJ-2021-05890},
      pages        = {1853 - 1868},
      year         = {2021},
      abstract     = {Neuronal aggregates of misfolded alpha-synuclein protein
                      are found in the brain and periphery of patients with
                      Parkinson’s disease. Braak and colleagues have
                      hypothesized that the initial formation of misfolded
                      alpha-synuclein may start in the gut, and then spread to the
                      brain via peripheral autonomic nerves hereby affecting
                      several organs, including the heart and intestine. Age is
                      considered the greatest risk factor for Parkinson’s
                      disease, but the effect of age on the formation of pathology
                      and its propagation has not been studied in detail. We aimed
                      to investigate whether propagation of alpha-synuclein
                      pathology from the gut to the brain is more efficient in old
                      versus young wild-type rats, upon gastrointestinal injection
                      of aggregated alpha-synuclein. Our results demonstrate a
                      robust age-dependent gut-to-brain and brain-to-gut spread of
                      alpha-synuclein pathology along the sympathetic and
                      parasympathetic nerves, resulting in age-dependent
                      dysfunction of the heart and stomach, as observed in
                      patients with Parkinson’s disease. Moreover,
                      alpha-synuclein pathology is more densely packed and
                      resistant to enzymatic digestion in old rats, indicating an
                      age-dependent maturation of alpha-synuclein aggregates. Our
                      study is the first to provide a detailed investigation of
                      alpha-synuclein pathology in several organs within one
                      animal model, including the brain, skin, heart, intestine,
                      spinal cord and autonomic ganglia. Taken together, our
                      findings suggest that age is a crucial factor for
                      alpha-synuclein aggregation and complete propagation to
                      heart, stomach and skin, similar to patients. Given that age
                      is the greatest risk factor for human Parkinson’s disease,
                      it seems likely that older experimental animals will yield
                      the most relevant and reliable findings. These results have
                      important implications for future research to optimize
                      diagnostics and therapeutics in Parkinson’s disease and
                      other age-associated synucleinopathies. Increased emphasis
                      should be placed on using aged animals in preclinical
                      studies and to elucidate the nature of age-dependent
                      interactions.},
      cin          = {IBI-7},
      ddc          = {610},
      cid          = {I:(DE-Juel1)IBI-7-20200312},
      pnm          = {5244 - Information Processing in Neuronal Networks
                      (POF4-524)},
      pid          = {G:(DE-HGF)POF4-5244},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:33880502},
      UT           = {WOS:000710929200029},
      doi          = {10.1093/brain/awab061},
      url          = {https://juser.fz-juelich.de/record/904320},
}