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J. Biol. Chem., Vol. 281, Issue 28, 19296-19304, July 14, 2006

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The Peptidylprolyl cis/trans-Isomerase Pin1 Modulates Stress-induced Dephosphorylation of Tau in Neurons

IMPLICATION IN A PATHOLOGICAL MECHANISM RELATED TO ALZHEIMER DISEASE^*

From the INSERM U815, Institut de Médecine Prédictive et Recherche Thérapeutique, 59045 Lille Cedex and Université Lille 2, School of Medicine, Place de Verdun, 59000 Lille, France

Deregulation of Tau phosphorylation is a key question in Alzheimer disease pathogenesis. Recently, Pin1, a peptidylprolyl cis/trans-isomerase, was proposed to be a new modulator in Tau phosphorylation in Alzheimer disease. In vitro, Pin1 was reported to present a high affinity for both Thr(P)-231, a crucial site for microtubule binding, and Thr(P)-212. In fact, Pin1 may facilitate Thr(P)-231 dephosphorylation by protein phosphatase 2A through trans isomerization of the Thr(P)-Pro peptide bound. However, whether Pin1 binding to Tau leads to isomerization of a single site or of multiple Ser/Thr(P)-Pro sites in vivo is still unknown. In the present study, Pin1 involvement was investigated in stress-induced Tau dephosphorylation with protein phosphatase 2A activation. Both oxidative (H₂O₂) and heat stresses induced hypophosphorylation of a large set of phospho-Tau epitopes in primary cortical cultures. In both cases, juglone, a Pin1 pharmacological inhibitor, partially prevented dephosphorylation of Tau at Thr-231 among a set of phosphoepitopes tested. Moreover, Pin1 is physiologically found in neurons and partially co-localized with Tau. Furthermore, in Pin1-deficient neuronal primary cultures, H₂O₂ stress-induced Tau dephosphorylation at Thr(P)-231 was significantly lower than in wild type neurons. Finally, Pin1 transfection in Pin1-deficient neuronal cell cultures allowed for rescuing the effect of H₂O₂ stress-induced Tau dephosphorylation, whereas a Pin1 catalytic mutant did not. This is the first demonstration of an in situ Pin1 involvement in a differential Tau dephosphorylation on the full-length multiphosphorylated substrate.

Received for publication, February 27, 2006 , and in revised form, May 2, 2006.

^* This work was supported by CNRS, Inserm, and grants from GIS Longévité and the European Community (APOPIS, LSHM-CT-2003-503330). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 33-320-622074; Fax: 33-3-20-62-20-79; E-mail: buee{at}lille.inserm.fr.

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