Figure 2.

Schematic of proposed mechanism for the toxicity of pThr¹⁷⁵tau. Under normal physiological conditions, tau is thought to exist in a closed paperclip conformation. Following phosphorylation of Thr¹⁷⁵ by a kinase or kinases yet to be defined, the closed paperclip structure opens sufficiently to allow for exposure of the PAD which in turn activates protein phosphatase 1 (PP1). PP1 in turn dephosphorylates Ser⁹ of GSK3β, allowing for increased pGSK3β by unmasking pTyr²¹⁶. pGSK3β in turn phosphorylates Thr²³¹tau in a process that does not require priming by phosphorylation of Ser²³⁵tau. It is not known whether pThr²³¹ exists in either the cis or trans isoform, but our evidence suggests that the presence of pThr²³¹ is associated with increased tau oligomer formation and its subsequent polymerization into tau fibrils.