Two major cellular pathways—the signaling kinase Akt and the protein quality control machinery involving Hsp90 with the ubiquitin ligase CHIP—collude to regulate levels of the microtubule binding protein tau. This is the take-home message of a new study from Chad Dickey of the University of South Florida in Tampa, and Leonard Petrucelli of the Mayo Clinic in Jacksonville, Florida. In the February 21 issue of PNAS online, the researchers show that Akt regulates tau degradation in multiple ways, both by regulating CHIP levels and by affecting tau phosphorylation. While the Akt pathway is well known for regulating tau phosphorylation, this is the first time the kinase has been implicated in controlling tau degradation. Both processes are important in the accumulation of abnormal tau that occurs in AD.
The CHIP/Hsp90 complex plays a central role in clearing tau and other misfolded, damaged, or toxic proteins. Proteins that cannot be refolded to their proper shapes by Hsp90 are ubiquitinated by CHIP and degraded in the proteasome. Inhibitors of the ATPase activity of Hsp90 steer client proteins, including tau, toward degradation and are being investigated as possible agents to stimulate clearance of abnormal proteins in neurodegenerative diseases (see ARF related news story). For a recent, broad review of the prospects for modulating protein quality control pathways to treat disease, see Balch et al., 2008.
In the new study, Dickey and colleagues show there is crosstalk between the CHIP-mediated degradation of tau and the Akt pathway. They use a variety of pharmacological treatments, siRNA, and cells from knockout mice to build the case that Akt and CHIP reciprocally regulate each other. In these systems, CHIP mediates Akt degradation, while Akt regulates CHIP levels.
From these results, the investigators wondered whether Akt affected degradation of tau, a CHIP client protein. Indeed, they found that downregulating Akt boosted CHIP-mediated tau degradation stimulated by an Hsp90 inhibitor. A likely explanation for this came when they looked at the effects of Akt on tau phosphorylation. Boosting Akt activity increased tau phosphorylation at two sites (S262/S356) that Dickey and coworkers had previously shown to prevent tau from binding to CHIP, thus blocking tau degradation. The sites are normally phosphorylated by the PAR1/MARK2 kinase, which has been implicated as an initiator kinase that begins the conversion of tau from normal to toxic protein in a fly model of tauopathy (see ARF related news story). One idea is that by blocking degradation, the S262/S356 phosphorylation promotes the accumulation of tau, which is then available for additional modification by other kinases, leading to hyperphosphorylation and aggregation.
The effects of Akt on tau phosphorylation led the investigators to ask whether Akt regulates PAR1/MARK2. Consistent with that possibility, they found that the proteins form a complex in cells, and that Akt knockout mice show decreased phosphorylation of tau at the PAR1/MARK2 sites in vivo. Further, Akt increased PAR1/MARK2-directed phosphorylation of tau in cotransfection experiments. Whether Akt acts directly on the PAR1/MARK2 kinase, or alternatively phosphorylates tau in a priming reaction that facilitates subsequent PAR1/MARK2 phosphorylation is not clear. That is something the lab is working on now, Petrucelli told ARF.
“Our findings suggest that Akt be considered in a novel context with regard to AD; rather than strictly serving as a modifier of tau phosphorylation, Akt likely serves a much more important role as a regulator of tau degradation,” the authors write. This means that changes in Akt activity, as have been reported in AD brain (Pei et al., 2003), could feed into tau stability and toxicity at several levels.—Pat McCaffrey