title: Cytoplasmic SET induces tau hyperphosphorylation through a decrease of methylated phosphatase 2A.
abstract: BACKGROUND
  The neuronal cytoplasmic localization of SET, an inhibitor of the phosphatase 2A (PP2A), results in tau hyperphosphorylation in the brains of Alzheimer patients through mechanisms that are still not well defined.
  
  
  RESULTS
  We used primary neurons and mouse brain slices to show that SET is translocated to the cytoplasm in a manner independent of both its cleavage and over-expression. The localization of SET in the cytoplasm, either by the translocation of endogenous SET or by internalization of the recombinant full-length SET protein, induced tau hyperphosphorylation. Cytoplasmic recombinant full-length SET in mouse brain slices induced a decrease of PP2A activity through a decrease of methylated PP2A levels. The levels of methylated PP2A were negatively correlated with tau hyperphosphorylation at Ser-202 but not with the abnormal phosphorylation of tau at Ser-422.
  
  
  CONCLUSIONS
  The presence of full-length SET in the neuronal cytoplasm is sufficient to impair PP2A methylation and activity, leading to tau hyperphosphorylation. In addition, our data suggest that tau hyperphosphorylation is regulated by different mechanisms at distinct sites. The translocation of SET to the neuronal cytoplasm, the low activity of PP2A, and tau hyperphosphorylation are associated in the brains of Alzheimer patients. Our data show a link between the translocation of SET in the cytoplasm and the decrease of methylated PP2A levels leading to a decrease of PP2A activity and tau hyperphosphorylation. This chain of events may contribute to the pathogenesis of Alzheimer disease.
authors: Stéphanie
authors: S
authors: Chasseigneaux
authors: Christine
authors: C
authors: Clamagirand
authors: Léa
authors: L
authors: Huguet
authors: Lucie
authors: L
authors: Gorisse-Hussonnois
authors: Christiane
authors: C
authors: Rose
authors: INSERM UMR 894, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France. bernadette.allinquant@inserm.fr.
authors: Bernadette
authors: B
authors: Allinquant
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D002478:Cells, Cultured; D003593:Cytoplasm; D004268:DNA-Binding Proteins; D015536:Down-Regulation; D056488:Histone Chaperones; D008297:Male; D008745:Methylation; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D015513:Oncogene Proteins / Q000378:metabolism*; D010766:Phosphorylation; D054648:Protein Phosphatase 2; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D056488:Histone Chaperones; D015513:Oncogene Proteins; C557500:SET protein, mouse; D016875:tau Proteins; D054648:Protein Phosphatase 2