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@ARTICLE{Younas:153365,
      author       = {Younas, Neelam and Zafar, Saima and Shafiq, Mohsin and
                      Noor, Aneeqa and Siegert, Anna and Arora, Amandeep Singh and
                      Galkin, Alexey and Zafar, Ayesha and Schmitz, Matthias and
                      Stadelmann, Christine and Andreoletti, Olivier and Ferrer,
                      Isidre and Zerr, Inga},
      title        = {{SFPQ} and {T}au: critical factors contributing to rapid
                      progression of {A}lzheimer's disease.},
      journal      = {Acta neuropathologica},
      volume       = {140},
      number       = {3},
      issn         = {1432-0533},
      address      = {Heidelberg},
      publisher    = {Springer},
      reportid     = {DZNE-2020-01362},
      pages        = {317 - 339},
      year         = {2020},
      abstract     = {Dysfunctional RNA-binding proteins (RBPs) have been
                      implicated in several neurodegenerative disorders. Recently,
                      this paradigm of RBPs has been extended to pathophysiology
                      of Alzheimer's disease (AD). Here, we identified disease
                      subtype specific variations in the RNA-binding proteome
                      (RBPome) of sporadic AD (spAD), rapidly progressive AD
                      (rpAD), and sporadic Creutzfeldt Jakob disease (sCJD), as
                      well as control cases using RNA pull-down assay in
                      combination with proteomics. We show that one of these
                      identified proteins, splicing factor proline and glutamine
                      rich (SFPQ), is downregulated in the post-mortem brains of
                      rapidly progressive AD patients, sCJD patients and 3xTg mice
                      brain at terminal stage of the disease. In contrast, the
                      expression of SFPQ was elevated at early stage of the
                      disease in the 3xTg mice, and in vitro after oxidative
                      stress stimuli. Strikingly, in rpAD patients' brains SFPQ
                      showed a significant dislocation from the nucleus and
                      cytoplasmic colocalization with TIA-1. Furthermore, in rpAD
                      brain lesions, SFPQ and p-tau showed extranuclear
                      colocalization. Of note, association between SFPQ and
                      tau-oligomers in rpAD brains suggests a possible role of
                      SFPQ in oligomerization and subsequent misfolding of tau
                      protein. In line with the findings from the human brain, our
                      in vitro study showed that SFPQ is recruited into
                      TIA-1-positive stress granules (SGs) after oxidative stress
                      induction, and colocalizes with tau/p-tau in these granules,
                      providing a possible mechanism of SFPQ dislocation through
                      pathological SGs. Furthermore, the expression of human tau
                      in vitro induced significant downregulation of SFPQ,
                      suggesting a causal role of tau in the downregulation of
                      SFPQ. The findings from the current study indicate that the
                      dysregulation and dislocation of SFPQ, the subsequent
                      DNA-related anomalies and aberrant dynamics of SGs in
                      association with pathological tau represents a critical
                      pathway which contributes to rapid progression of AD.},
      keywords     = {Alzheimer Disease: metabolism / Alzheimer Disease:
                      pathology / Animals / Brain: metabolism / Brain: pathology /
                      Creutzfeldt-Jakob Syndrome: metabolism / Cytoplasm:
                      metabolism / Down-Regulation: physiology / Humans / Mice,
                      Transgenic / PTB-Associated Splicing Factor: metabolism /
                      RNA-Binding Proteins: genetics / RNA-Binding Proteins:
                      metabolism / tau Proteins: metabolism},
      cin          = {Ext UMG Zerr / AG Zerr / Göttingen Pre 2020},
      ddc          = {610},
      cid          = {I:(DE-2719)5000037 / I:(DE-2719)1440011-1 /
                      I:(DE-2719)6000014},
      pnm          = {344 - Clinical and Health Care Research (POF3-344)},
      pid          = {G:(DE-HGF)POF3-344},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:32577828},
      pmc          = {pmc:PMC7423812},
      doi          = {10.1007/s00401-020-02178-y},
      url          = {https://pub.dzne.de/record/153365},
}