FKBP52 is a member of the FKBP (FK506-binding protein) family of peptidyl prolyl cis-trans isomerases and has recently been shown to control chemotropic guidance of neuronal growth cones via regulation of TRPC1 channel opening in the developing spinal cord. Chambraud et al. reported that FKBP52 interacts with tau, [...continued] especially when the latter is in its hyperphosphorylated form, and that FKBP52 and tau colocalize in the distal part of the axons of cortical neurons.

Tau functions at two major stages in the brain: during brain development and brain aging. Dynamic tau phosphorylation occurs during embryonic development, which may play an important role in refining or maintaining neuronal structure and function, whereas tau hyperphosphorylation affects tau function and degradation, leading to tangle formation and neurodegeneration in tauopathies (4). Interestingly, Chambraud et al. found that FKBP52 inhibits the ability of recombinant tau to promote microtubule assembly in vitro. Moreover, overexpression of FKBP52 in differentiating PC12 cells prevents tau accumulation and reduces neurite outgrowth. These results demonstrate that FKBP52 has an inhibitory effect on neuronal differentiation/development and suggest that FKBP52 may be a promoting factor of tauopathy. The latter possibility is especially exciting given that FKBP inhibitors, which are clinically used as immunosuppressive drugs, have been shown to have neuroprotective effects.

Strikingly, these effects of FKBP52 on tau are in sharp contrast to those of Pin1, an another, but distinct peptidyl prolyl cis-trans isomerase (5-8). Pin1 binds to and isomerizes the phosphorylated Thr231-Pro motif in tau to restore tau ability to bind microtubules and to promote their assembly (9), to facilitate tau dephosphorylation by PP2A (10,11), and to promote tau degradation (12). The impact of Pin1 on tauopathy and neurodegeneration has been well established. Pin1 is inhibited by multiple mechanisms in the Alzheimer brain in humans, and deletion of Pin1 in mice causes progressive age-dependent tauopathy (2,10). Moreover, postnatal neuronal Pin1 overexpression effectively inhibits the tauopathy phenotype induced by overexpression of wild-type tau in transgenic mice (1,2). These results demonstrate a pivotal role of Pin1 in protecting against tauopathy in Alzheimer disease.

Although both Pin1 and FKBP52 have peptidyl-prolyl isomerase (PPIase) activity and a specific protein-protein interaction domain (2), they seem to have the opposite effects on tau functions. It is not clear why they have such opposite effects on tau. Notably, Pin1 specifically isomerizes only phosphorylated Ser/Thr-Pro motifs and acts only on phosphorylated tau, but FKBP52 has much less activity towards a Ser/Thr-Pro motif after phosphorylation (7), and Chambraud et al. show it can inhibit the function of non-phosphorylated tau. One interesting possibility is that FKBP52 might act directly on non-phosphorylated tau, although its binding to tau seems to be enhanced by tau hyperphosphorylation. Future studies on how FKBP52 regulates tau protein conformation and function, and whether manipulating FKBP52 affects tauopathy in animal models might help offer new insight into tau regulation and provide potential new approaches to inhibit tauopathies.

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