title: Immunophilin FKBP52 induces Tau-P301L filamentous assembly in vitro and modulates its activity in a model of tauopathy.
abstract: The Tau protein is the major component of intracellular filaments observed in a number of neurodegenerative diseases known as tauopathies. The pathological mutant of Tau containing a proline-to-leucine mutation at position 301 (P301L) leads to severe human tauopathy. Here, we assess the impact of FK506-binding protein with a molecular mass of ∼52 kDa (FKBP52), an immunophilin protein that interacts with physiological Tau, on Tau-P301L activity. We identify a direct interaction of FKBP52 with Tau-P301L and its phosphorylated forms and demonstrate FKBP52's ability to induce the formation of Tau-P301L oligomers. EM analysis shows that Tau-P301L oligomers, induced by FKBP52, can assemble into filaments. In the transgenic zebrafish expressing the human Tau-P301L mutant, FKBP52 knockdown is sufficient to redrive defective axonal outgrowth and branching related to Tau-P301L expression in spinal primary motoneurons. This result correlates with a significant reduction of pT181 pathological phosphorylated Tau and with recovery of the stereotypic escape response behavior. Collectively, FKBP52 appears to be an endogenous candidate that directly interacts with the pathogenic Tau-P301L and modulates its function in vitro and in vivo.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 788, Université Paris XI, 94276 Le Kremlin Bicêtre, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Giustiniani
authors.forename: Béatrice
authors.initials: B
authors.lastname: Chambraud
authors.forename: Elodie
authors.initials: E
authors.lastname: Sardin
authors.forename: Omar
authors.initials: O
authors.lastname: Dounane
authors.forename: Kevin
authors.initials: K
authors.lastname: Guillemeau
authors.forename: Hiroko
authors.initials: H
authors.lastname: Nakatani
authors.forename: Dominik
authors.initials: D
authors.lastname: Paquet
authors.forename: Amina
authors.initials: A
authors.lastname: Kamah
authors.forename: Isabelle
authors.initials: I
authors.lastname: Landrieu
authors.forename: Guy
authors.initials: G
authors.lastname: Lippens
authors.forename: Etienne-Emile
authors.initials: EE
authors.lastname: Baulieu
authors.forename: Marcel
authors.initials: M
authors.lastname: Tawk
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001704:Biopolymers / Q000378:metabolism; D016923:Cell Death / Q000235:genetics; D002460:Cell Line; D055785:Gene Knockdown Techniques; D006801:Humans; D066298:In Vitro Techniques; D008954:Models, Biological; D009046:Motor Neurons / Q000378:metabolism; D010766:Phosphorylation; D013239:Stereotyped Behavior; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D024801:Tauopathies / Q000473:pathology* / Q000503:physiopathology; D015027:Zebrafish / Q000502:physiology; D016875:tau Proteins / Q000378:metabolism / Q000502:physiology*
chemical_list: D001704:Biopolymers; D016875:tau Proteins; D022021:Tacrolimus Binding Proteins; C403485:tacrolimus binding protein 4
keywords: FKBP; Tau assembly; Tau-P301L dementia