The FTDP-17-linked mutation R406W abolishes the interaction of phosphorylated tau with microtubules

The recent finding that several point mutations in the gene encoding for th e microtubule-binding protein tau correlate with neurological disorders has heightened interest in the mechanisms of destabilization of this protein. In this study the functional consequences of the tau mutation R406W on the interaction of the protein with microtubules have been analyzed. Mutated ta u is less phosphorylated than its normal counterpart at serines 396 and 404 . Furthermore, the phosphorylated mutant protein is unable to bind to micro tubules, and, as a consequence, microtubules assembled after transient noco dazole treatment in the presence of this tau variant contain only unmodifie d tau and appear to form more and longer bundles than those assembled in th e presence of wild-type tau. We propose that phosphorylated tau, unbound to microtubules, could accumulate in the cytoplasm.