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@ARTICLE{Kim:165570,
      author       = {Kim, Yoon A and Siddiqui, Tohid and Blaze, Jennifer and
                      Cosacak, Mehmet Ilyas and Winters, Tristan and Kumar, Atul
                      and Tein, Ellen and Sproul, Andrew A and Teich, Andrew F and
                      Bartolini, Francesca and Akbarian, Schahram and Kizil,
                      Caghan and Hargus, Gunnar and Santa-Maria, Ismael},
      title        = {{RNA} methyltransferase {NS}un2 deficiency promotes
                      neurodegeneration through epitranscriptomic regulation of
                      tau phosphorylation.},
      journal      = {Acta neuropathologica},
      volume       = {145},
      number       = {1},
      issn         = {0001-6322},
      address      = {Heidelberg},
      publisher    = {Springer},
      reportid     = {DZNE-2022-01710},
      pages        = {29 - 48},
      year         = {2023},
      abstract     = {Epitranscriptomic regulation adds a layer of
                      post-transcriptional control to brain function during
                      development and adulthood. The identification of
                      RNA-modifying enzymes has opened the possibility of
                      investigating the role epitranscriptomic changes play in the
                      disease process. NOP2/Sun RNA methyltransferase 2 (NSun2) is
                      one of the few known brain-enriched methyltransferases able
                      to methylate mammalian non-coding RNAs. NSun2 loss of
                      function due to autosomal-recessive mutations has been
                      associated with neurological abnormalities in humans. Here,
                      we show NSun2 is expressed in adult human neurons in the
                      hippocampal formation and prefrontal cortex. Strikingly, we
                      unravel decreased NSun2 protein expression and an increased
                      ratio of pTau/NSun2 in the brains of patients with
                      Alzheimer's disease (AD) as demonstrated by Western blotting
                      and immunostaining, respectively. In a well-established
                      Drosophila melanogaster model of tau-induced toxicity,
                      reduction of NSun2 exacerbated tau toxicity, while
                      overexpression of NSun2 partially abrogated the toxic
                      effects. Conditional ablation of NSun2 in the mouse brain
                      promoted a decrease in the miR-125b m6A levels and tau
                      hyperphosphorylation. Utilizing human induced pluripotent
                      stem cell (iPSC)-derived neuronal cultures, we confirmed
                      NSun2 deficiency results in tau hyperphosphorylation. We
                      also found that neuronal NSun2 levels decrease in response
                      to amyloid-beta oligomers (AβO). Notably, AβO-induced tau
                      phosphorylation and cell toxicity in human neurons could be
                      rescued by overexpression of NSun2. Altogether, these
                      results indicate that neuronal NSun2 deficiency promotes
                      dysregulation of miR-125b and tau phosphorylation in AD and
                      highlights a novel avenue for therapeutic targeting.},
      keywords     = {Mice / Animals / Humans / Adult / Methyltransferases:
                      genetics / Phosphorylation: genetics / Drosophila
                      melanogaster: genetics / Drosophila melanogaster: metabolism
                      / Induced Pluripotent Stem Cells: metabolism / Alzheimer
                      Disease: genetics / Alzheimer Disease: metabolism /
                      MicroRNAs: genetics / tau Proteins: metabolism / Mammals:
                      metabolism / Alzheimer’s disease (Other) / Methylation
                      (Other) / MicroRNA (Other) / NSun2 (Other) /
                      Neurodegeneration (Other) / Tau phosphorylation (Other)},
      cin          = {AG Kizil},
      ddc          = {610},
      cid          = {I:(DE-2719)1710007},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pmc          = {pmc:PMC9807547},
      pubmed       = {pmid:36357715},
      doi          = {10.1007/s00401-022-02511-7},
      url          = {https://pub.dzne.de/record/165570},
}