Question:

Present models for the intracellular transport of Tau protein in neurons suggest motor protein dependent co-transport with microtubule fragments and diffusion of Tau in the cytoplasm, while Tau is believed to be stationary when bound to microtubules and in equilibrium with free diffusion in the cytosol. Observations that members of the microtubule-dependent kinesin motor family show Brownian motion along microtubules led us to hypothesize that diffusion along microtubules could also be relevant in the case of Tau.

Methods:

We used single molecule TIRF microscopy to probe for diffusion of individual fluorescently labelled Tau molecules along microtubules.

Results:

We found that individually detected Tau molecules were able to diffuse along microtubules over distances up to several micrometers. Surprisingly, diffusion parameters such as diffusion coefficient, interaction time, and scanned microtubule length did not change with Tau concentration. Tau binding and diffusion along the microtubule lattice, however, were sensitive to ionic strength and pH and drastically reduced upon enzymatic removal of the negatively charged carboxy termini of tubulin. Competition between Tau and kinesin molecules for these c-termini might also explain the observed inhibitory effect of pathological high Tau concentrations on kinesin function.

Conclusions:

We propose one-dimensional Tau diffusion guided by the microtubule lattice as one possible additional mechanism for Tau distribution in cells. By such one-dimensional microtubule lattice diffusion, Tau could be guided to both microtubule ends, i.e. the sites where Tau is needed during microtubule polymerisation, independently of directed motor-dependent transport. This could be important in conditions where active transport along microtubules might be compromised.