Fig. 7. Effect of FTLD mutations on the fibrillization pathway.
Normal tau binds tightly to microtubules, but dissociates upon phosphorylation to form free tau, which exists as a natively disordered, assembly incompetent monomer (Ux). A conformational change to an assembly competent state accelerates polymerization (Uc). Once assembly competent species form, the rate-limiting step in tau fibrillization is formation of dimer, which represents the thermodynamic nucleus (N). Following nucleation, extension occurs through further addition of assembly competent monomers to the filament (F) ends. Tau mutations promote fibrillization at multiple points in the pathway. Reactions characterized herein are shown in green lettering, whereas those reported in the literature are shown in red lettering. See text for details.