Modulation of tau phosphorylation and intracellular localization by cellular stress

Tau is a microtubule-associated protein that is functionally modulated by p hosphorylation and hyperphosphorylated in several neurodegenerative disease s. Because phosphorylation regulates both normal and pathological tau funct ioning, it is of great interest to identify the signalling pathways and enz ymes capable of modulating tau phosphorylation in vivo. The present study e xamined changes in tau phosphorylation and localization in response to osmo tic stress, which activates the stress-activated protein kinases (SAPKs), a family of proline-directed protein kinases shown to phosphorylate tau in v itro and hypothesized to phosphorylate tau in Alzheimer's disease. Immunobl ot analysis with phosphorylation-dependent antibodies revealed that osmotic stress increased tau phosphorylation at the non-Ser/Thr-Pro sites Ser-262/ 356, within the microtubule-binding domain, as well as Ser/Thr-Pro sites ou tside of tau's microtubule-binding domain. Although an SAPKs examined were activated by osmotic stress, none of the endogenous SAPKs mediated the incr ease in tau phosphorylation. However, when transfected into SH-SY5Y cells, SAPK3, but not the other SAPKs examined, phosphorylated tau in situ in resp onse to activation by osmotic stress. Osmotic-stress-induced tau phosphoryl ation correlated with a decrease in the amount of tau associated with the c ytoskeleton and an increase in the amount of soluble tau. This stress-induc ed alteration in tau localization was only partially due to phosphorylation at Ser-262/356 by a staurosporine-sensitive, non-proline-directed, protein kinase. Taken together, these results suggest that osmotic stress activate s at least two tau-directed protein kinases, one proline-directed and one n onproline-directed, that SAPK3 can phosphorylate tau on Ser/Thr-Pro residue s in situ, and that Ser-262/356 phosphorylation only partially regulates ta u localization in the cell.