title: Molecular implication of PP2A and Pin1 in the Alzheimer's disease specific hyperphosphorylation of Tau.
abstract: BACKGROUND
  Tau phosphorylation and dephosphorylation regulate in a poorly understood manner its physiological role of microtubule stabilization, and equally its integration in Alzheimer disease (AD) related fibrils. A specific phospho-pattern will result from the balance between kinases and phosphatases. The heterotrimeric Protein Phosphatase type 2A encompassing regulatory subunit PR55/Bα (PP2A(T55α)) is a major Tau phosphatase in vivo, which contributes to its final phosphorylation state. We use NMR spectroscopy to determine the dephosphorylation rates of phospho-Tau by this major brain phosphatase, and present site-specific and kinetic data for the individual sites including the pS202/pT205 AT8 and pT231 AT180 phospho-epitopes.
  
  
  RESULTS
  We demonstrate the importance of the PR55/Bα regulatory subunit of PP2A within this enzymatic process, and show that, unexpectedly, phosphorylation at the pT231 AT180 site negatively interferes with the dephosphorylation of the pS202/pT205 AT8 site. This inhibitory effect can be released by the phosphorylation dependent prolyl cis/trans isomerase Pin1. Because the stimulatory effect is lost with the dimeric PP2A core enzyme (PP2A(D)) or with a phospho-Tau T231A mutant, we propose that Pin1 regulates the interaction between the PR55/Bα subunit and the AT180 phospho-epitope on Tau.
  
  
  CONCLUSIONS
  Our results show that phosphorylation of T231 (AT180) can negatively influence the dephosphorylation of the pS202/pT205 AT8 epitope, even without an altered PP2A pool. Thus, a priming dephosphorylation of pT231 AT180 is required for efficient PP2A(T55α)-mediated dephosphorylation of pS202/pT205 AT8. The sophisticated interplay between priming mechanisms reported for certain Tau kinases and the one described here for Tau phosphatase PP2A(T55α) may contribute to the hyperphosphorylation of Tau observed in AD neurons.
authors: CNRS-UMR 8576, Federative Research Institute IFR 147, University of Lille-North of France, Villeneuve d'Ascq, France. isabelle.landrieu@univ-lille1.fr
authors: Isabelle
authors: I
authors: Landrieu
authors: Caroline
authors: C
authors: Smet-Nocca
authors: Laziza
authors: L
authors: Amniai
authors: Justin Vijay
authors: JV
authors: Louis
authors: Jean-Michel
authors: JM
authors: Wieruszeski
authors: Jozef
authors: J
authors: Goris
authors: Veerle
authors: V
authors: Janssens
authors: Guy
authors: G
authors: Lippens
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology* / Q000473:pathology; D000595:Amino Acid Sequence; D000818:Animals; D019925:Cyclin A / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D000939:Epitopes / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000378:metabolism*; D010766:Phosphorylation; D055503:Protein Multimerization; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D011817:Rabbits; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D019925:Cyclin A; D000939:Epitopes; D050505:Mutant Proteins; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D016875:tau Proteins; D051357:Cyclin-Dependent Kinase 2; D054648:Protein Phosphatase 2; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase