A role for FKBP52 in Tau protein function

Abstract

Tau is a microtubule-associated protein, which is widely expressed in the central nervous system, predominantly in neurons, where it regulates microtubule dynamics, axonal transport, and neurite outgrowth. The aberrant assembly of Tau is the hallmark of several human neurodegenerative diseases, collectively known as tauopathies. They include Alzheimer’s disease, Pick’s disease, progressive supranuclear palsy, and frontotemporal dementia and parkinsonism linked to chromosome 17. Several abnormalities in Tau, such as hyperphosphorylation and aggregation, alter its function and are central to the pathogenic process. Here, we describe biochemical and functional interactions between FKBP52 and Tau. FKBP52 is a member of the FKBP (FK506-binding protein) family that comprises intracellular protein effectors of immunosuppressive drugs (such as FK506 and rapamycin). We found that FKBP52, which is abundant in brain, binds directly and specifically to Tau, especially in its hyperphosphorylated form. The relevance of this observation was confirmed by the colocalization of both proteins in the distal part of the axons of cortical neurons and by the antagonistic effect of FKBP52 on the ability of Tau to promote microtubule assembly. Overexpression of FKBP52 in differentiated PC12 cells prevented the accumulation of Tau and resulted in reduced neurite length. Taken together, these findings indicate a role for FKBP52 in Tau function and may help to decipher and modulate the events involved in Tau-induced neurodegeneration.

Sodium selenate mitigates tau pathology, neurodegeneration, and functional deficits in Alzheimer's disease models

“…Importantly, targeting tau extends treatment to tau-only dementias, of which there are many. Current strategies in developing tau-directed treatments include inhibition of tau aggregation (34)(35)(36)(37)(38), stabilization of microtubules (39,40), inhibition of kinases (41,42), induction of tau clearance (43)(44)(45), immunotherapy (46), and indirect modulation of tau function (47). So far, however, only a limited number of compounds proved efficacy in tau transgenic mouse models, and even fewer progressed into clinical trials (13).…”

Comparative Analysis of Different Peptidyl-Prolyl Isomerases Reveals FK506-binding Protein 12 as the Most Potent Enhancer of α-Synuclein Aggregation

“…By catalyzing the cistrans isomerization of some peptide bonds (Ser(P)/Thr(P)-Pro) in Tau protein, Pin1 restores the ability of phosphorylated Tau to bind microtubules and promotes tau dephosphorylation by the PP2A phosphatase (33,34). Although there is still some controversy in the field, Pin1 is also believed to interact with the C-terminal domain of the amyloid precursor protein (APP) via recognition of the phosphorylated Thr-688, influencing APP metabolism and toxic A␤ production (35)(36)(37). In contrast to the increasing evidence that Pin1 is crucial in the pathogenesis of Alzheimer disease, little is yet known about its involvement in PD.…”

Biochemistry and Cell Biology of Tau Protein in Neurofibrillary Degeneration

“…However, it is noteworthy that the repeat domain possesses two motifs of the consensus type KVERQ, which interact with hsc70 for chaperonemediated autophagy (Wang et al 2009). Other interactors of Tau are linked to chaperone components, for example the prolyl isomerase Pin-1 (Liou et al 2003), FKBP51, FKBP52 (Chambraud et al 2010;Jinwal et al 2010). Pin-1 isomerizes the motifs pT212-P and pS231-P in the proline-rich domain from cis to trans and thus allows the dephosphorylation by PP-2a and recovery of microtubule binding (Smet et al 2004).…”

“…Through heat shock proteins (HSP) Chambraud et al (2010) Continued colocalization by microscopy, coassembly, yeast 2-hybrid, etc.). By far the most predominant interaction of Tau is that with microtubules, so that the microtubule network can effectively be imaged by fluorescently labeled Tau, and Tau becomes randomized when MTs break down (curiously, databases of protein -protein interactions tend to ignore this major interaction partner of Tau).…”