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@PHDTHESIS{Lohmann:155350,
      author       = {Lohmann, Stephanie},
      title        = {{N}euroinvasion and cerebral ischemia as possible sources
                      for alpha-synuclein prions in {P}arkinson's disease},
      school       = {Rheinische Friedrich-Wilhelms-Universität Bonn},
      type         = {Dissertation},
      reportid     = {DZNE-2021-00617},
      pages        = {88 pages, 24 figures, 7 tables},
      year         = {2021},
      note         = {Dissertation, Rheinische Friedrich-Wilhelms-Universität
                      Bonn, 2021},
      abstract     = {In synucleinopathies such as Parkinson's disease misfolding
                      of a-synuclein, normally a cellular and soluble protein,
                      leads to the accumulation of insoluble protein aggregates
                      and to central nervous system disease (CNS). Misfolded
                      a-synuclein acts as a seed, by recruiting native a-synuclein
                      and inducing its misfolding into insoluble a-synuclein
                      aggregates. Aggregated a-synuclein shows prion-like
                      characteristics and spreads via cell-to-cell transmission
                      throughout the central nervous system but also within the
                      periphery, ultimately causing neurological disease.Because
                      the spatiotemporal spreading of pathological a-synuclein
                      from the periphery to the CNS is not fully elucidated this
                      work investigated and compared the spreading of pathological
                      a-synuclein after intravenous or oral inoculation with that
                      after intracerebral or intraperitoneal inoculation of
                      TgM83+1- mice overexpressing the A53T mutant of human
                      a-synuclein with a-synuclein fibrils. In accordance with
                      previous studies, an infection rate of $100\%$ was observed
                      for intracerebrally and intraperitoneally injected mice.
                      Moreover, this study is the first to show that a single
                      intravenous injection of a-synuclein fibrils causes
                      synucleinopathy in $100\%$ of the challenged mice, and even
                      a single oral gavage with a-synuclein fibrils results in
                      $50\%$ of the challenged mice in neurological disease.
                      Diseased mice displayed aggregates of sarkosyl-insoluble and
                      phosphorylated a-synuclein, which colocalized with ubiquitin
                      and p62 and were accompanied by gliosis, indicative of
                      neuroinflammation, throughout the CNS. In contrast, none of
                      the control mice that were challenged with bovine serum
                      albumin via the same routes developed any neurological
                      disease or neuropathology. These findings show that
                      aggregated a-synuclein behaves like a prion causing
                      neuropathology and CNS disease, not only after intracerebral
                      or intraperitoneal challenge but also by neuroinvasion after
                      a single intravenous, or oral challenge.Since cerebral
                      ischemia increases the risk of developing Parkinson's
                      disease (PD) without being clear what the underlying
                      mechanism is, the second aim of this work was to study the
                      impact of ischemic stroke on a-synuclein aggregation, which
                      is known to cause PD. To investigate post-ischemic changes
                      to the CNS, focal cerebral ischemia was induced by middle
                      cerebral artery occlusion (MCAO) in transgenic mice
                      overexpressing the A53T mutant of human of a-synuclein.
                      lschemic mice displayed significant motor deficits and lass
                      of dopaminergic neurons in the substantia nigra at 360 days
                      after MCAO. This was caused by a significantly increased
                      amount of aggregated a-synuclein, which was accompanied by
                      neuroinflammation as indicated by astrogliosis and
                      microgliosis. In summary, cerebral ischemia induced a
                      synucleinopathy with lass of dopaminergic neurons in the
                      substantia nigra resulting in motor deficits in a mouse
                      model of PD, which may explain why cerebral ischemia
                      increases the risk of PD.},
      cin          = {AG Vorberg},
      cid          = {I:(DE-2719)1013004},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)11},
      urn          = {urn:nbn:de:hbz:5-63044},
      url          = {https://pub.dzne.de/record/155350},
}