Title

The Hsp90 cochaperone, FKBP51, increases Tau stability and polymerizes microtubules.

Journal

The Journal of neuroscience : the official journal of the Society for Neuroscience

Volume

30

Issue

None

Pages

591-9

Date

2010-01-13

Authors

Dickey CA | Blair LJ | Koren J 3rd | Jinwal UK | Abisambra JF | Jin Y | Johnson AG | Jones JR | O'Leary JC 3rd | Borysov SI | Buchner J | Cox MB | Schmid AB | Shults CL

We then investigated what effect over-expression or knockdown of FKBP51 might have on the interaction of tau with other Hsp90 cochaperones that comprise a mature Hsp90 complex. Surprisingly, we found that FKBP51 over-expression decreased the endogenous association of another Hsp90 pro-folding cochaperone, Aha1, with tau despite increasing Hsp90 binding (Fig. 4C). Endogenous p23 binding to tau however was not detected. Conversely, knockdown of FKBP51 with siRNA increased the association of endogenous Aha1 with tau despite decreasing the number of Hsp90 tau complexes. Moreover, endogenous p23 binding to tau was only detectable when FKBP51 was knocked down (Fig. 4C).

We found that FKBP51 indeed could interact with tau from both AD patients and control cases (Fig. 3D), further suggesting a functionally relevant relationship between FKBP51 and tau. We then investigated whether FKBP51 would preferentially interact with phosphorylated tau species. We increased the number of samples per group (4 for AD and 4 for normal) and again co-immunoprecipitated FKBP51. After gel electrophoresis, immunoblotting showed increased association of pS396 and pS199-S202 tau species with FKBP51 in AD tissue (Fig S1). Indeed, we found that FKBP51 over-expression increased phospho- and total tau levels (by 80%) in HeLa cells stably expressing normal human tau, while FKBP52 over-expression had no affect (Fig.4A). These experiments were repeated multiple times and Student t-test of these replicates demonstrated that FKBP51 significantly increased total tau levels (p= 0.0104).

Fluorescent imaging of these extracts revealed that wildtype FKBP51 promoted microtubule polymerization relative to extracts treated with buffer only (Fig 7A and S2). Conversely, neither mutant F130A FKBP51 nor FKBP52 stimulated microtubule formation.

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