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@ARTICLE{Yamada:141674,
      author       = {Yamada, Elizabeth S and Respondek, Gesine and Müssner,
                      Stefanie and de Andrade, Anderson and Höllerhage, Matthias
                      and Depienne, Christel and Rastetter, Agnès and Tarze,
                      Agathe and Friguet, Bertrand and Salama, Mahmoud Elhussiny
                      Abdelhaleen and Champy, Pierre and Oertel, Wolfgang H and
                      Höglinger, Günter},
      title        = {{A}nnonacin, a natural lipophilic mitochondrial complex {I}
                      inhibitor, increases phosphorylation of tau in the brain of
                      {FTDP}-17 transgenic mice.},
      journal      = {Experimental neurology},
      volume       = {253},
      issn         = {0014-4886},
      address      = {Orlando, Fla.},
      publisher    = {Academic Press},
      reportid     = {DZNE-2020-00005},
      pages        = {113-125},
      year         = {2014},
      abstract     = {Both genetic and environmental factors likely contribute to
                      the neuropathology of tauopathies, but it remains unclear
                      how specific genetic backgrounds affect the susceptibility
                      towards environmental toxins. Mutations in the tau gene have
                      been associated with familial tauopathies, while annonacin,
                      a plant-derived mitochondrial inhibitor, has been implicated
                      in an environmental form of tauopathy. We therefore
                      determined whether there was a pathogenic synergy between
                      annonacin exposure and the expression of the R406W-tau
                      mutation in transgenic mice. We found that annonacin
                      exposure caused an increase in the number of neurons with
                      phosphorylated tau in the somatodendritic compartment in
                      several brain areas in R406W(+/+) mice as opposed to mice
                      that had only the endogenous mouse tau (R406W(-/-)). Western
                      blot analysis demonstrated a concomitant increase in total
                      tau protein without increase in tau mRNA, but reduced
                      proteasomal proteolytic activity in R406W(+/+), but not
                      R406W(-/-) mice, upon annonacin-treatment. Phosphorylated
                      tau levels exceeded the increase in total tau protein, along
                      with increased levels of different tau kinases, foremost a
                      striking increase in the p25/p35 ratio, known to activate
                      the tau kinase Cdk5. In summary, we observed a synergistic
                      interaction between annonacin exposure and the presence of
                      the R406W-tau mutation, which resulted in reduced
                      degradation, increased phosphorylation and redistribution of
                      neuronal tau.},
      keywords     = {Animals / Arginine: genetics / Brain: drug effects / Brain:
                      metabolism / Dose-Response Relationship, Drug / Enzyme
                      Inhibitors: pharmacology / Furans: pharmacology / Gene
                      Expression Regulation: drug effects / Gene Expression
                      Regulation: genetics / Humans / Lactones: pharmacology /
                      Mice / Mice, Inbred C57BL / Mice, Transgenic / Microglia:
                      drug effects / Microtubule-Associated Proteins: metabolism /
                      Mitochondria: genetics / Mitochondria: metabolism /
                      Mortality / Mutation: genetics / Neurons: drug effects /
                      Phosphorylation: drug effects / Phosphorylation: genetics /
                      Tryptophan: genetics / tau Proteins: genetics / Enzyme
                      Inhibitors (NLM Chemicals) / Furans (NLM Chemicals) /
                      Lactones (NLM Chemicals) / MAPT protein, human (NLM
                      Chemicals) / Microtubule-Associated Proteins (NLM Chemicals)
                      / tau Proteins (NLM Chemicals) / annonacin (NLM Chemicals) /
                      Tryptophan (NLM Chemicals) / Arginine (NLM Chemicals)},
      cin          = {AG Höglinger 1},
      ddc          = {610},
      cid          = {I:(DE-2719)1110002},
      pnm          = {344 - Clinical and Health Care Research (POF3-344)},
      pid          = {G:(DE-HGF)POF3-344},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:24389273},
      doi          = {10.1016/j.expneurol.2013.12.017},
      url          = {https://pub.dzne.de/record/141674},
}