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 prolineto-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.FKBP | Tau assembly | Tau-P301L dementia T au is a MAP mainly found in neurons (1, 2), which becomes hyperphosphorylated in several neurodegenerative diseases known as tauopathies and forms intraneuronal aggregates called neurofibrillary tangles (NFTs) (3-5). The accumulation of Tau aggregates is a multistep process that involves transient species, and growing evidence suggests that not only the NFTs but equally small oligomeric species contribute to Tau-mediated neurotoxicity (6-8). The pathological mutant of Tau containing a proline-to-leucine mutation at position 301 (P301L) is identified in frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17) (9). Larvae of the zebrafish overexpressing the Tau-P301L mutant protein show defects in motoneuron development early on, and in this model, different Tau phosphoforms are associated with its pathological state (10).The FK506-binding protein with a molecular mass of ∼52 kDa (FKBP52) belongs to the immunophilin family and presents rotamase activity inhibited by FK506 binding (11). This enzymatic activity catalyzes the isomerization of peptidyl-prolyl bonds between cis and trans conformations, and therefore influences target protein folding and function (12, 13). FKBP52 contains additional functional domains, such as a tetratricopeptide repeat domain that serves as a binding site for molecular chaperone heat shock protein with a molecular mass of 90 kDa (14) and for which chaperone activity was observed (15).A novel role of FKBP52 has recently emerged because it binds directly to tubulin and induces tubulin depolymerization in vitro (16). Biochemical characterization of FKBP52 showed that it interacts with Tau, especially its hyperphosphorylated form, and demonstrated an antagonist effect of FKBP52 on Tau's function in tubulin assembly ...

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