Abstract: Methods of screening for candidate compounds capable of inhibiting activity of fyn in phosphorylating tau protein at Y394 or binding to fyn to inhibit interaction with tau protein at Y394, including determining whether, and optionally the extent, the candidate compounds have these capabilities under conditions where fyn has these capabilities in the absence of the candidate compound. Methods of screening for substances capable of promoting dephosphorylation of tau protein by a phosphatase at a site of tau protein including contacting a candidate substance, the tau protein and a phosphatase capable of dephosphorylating the tau protein under conditions where the phosphatase is capable of dephosphorylating the site in absence of the candidate substance, where the kinase is fyn; determining whether, and optionally the extent, the candidate substance promotes dephosphorylation of the tau protein at the site; and selecting the candidate substance which promotes dephosphorylation of the tau protein the sites.

Abstract: Methods for screening for substances capable of modulating the phosphorylation of tau protein are disclosed, and in particular paired helical filament (PHF) tau, and the use of such modulators in the treatment of tauopathies. The assays and screening methods are based on the identification of new phosphorylation sites in PHF tau and new kinases and combinations of kinases as therapeutic targets, in particular the identification of casein kinase 1 as a kinase which phosphorylates tau protein.