Role of the amino terminus

We have shown that the microtubule binding repeat region is essential for tau polymerization and that truncations of the carboxy terminus enhance polymerization (Post-translational Modifications and Role of the carboxy terminus). That the amino terminus also has a role in the formation of tau filaments is indicated by the appearance of the Alz 50 conformation early in the progression of AD neuropathology: in this conformation, the amino terminus interacts with the microtubule binding region (see Carmel, et al). With the recent discovery of a case of frontotemporal dementia (Tau Neuropathology) bearing a mutation in the amino-terminal region of the tau molecule (Arg5 to Leu, R5L), it became imperative to examine this region of the molecule.

We generated two tau constructs altered in this region: R5L and a deletion mutant lacking residues 2-18 (D2-18), and tested their ability to polymerize in our in vitro system. We could not use laser light scattering to assess polymerization because the filaments formed were too short to scatter light efficiently. Instead, we monitored filament assembly by quantitative electron microscopy. Both mutants produced filaments that were on average less than half as long as wild-type. The D2-18 molecule produced about the same number of filaments as wild-type, and because the filaments were shorter, less total mass of polymerized material. On the other hand, the R5L mutant produced more than four times the number of filaments as wild-type, resulting in a greater mass of polymerized tau.

Thus, we conclude that the amino terminus facilitates tau polymerization. This facilitating role is apparently enhanced by the R5L mutation, and this enhancement could drive the formation of neuropathological structures in this form of frontotemporal dementia. These findings also emphasize the importance of Alz 50 reactivity and altered tau conformation in neurodegenerative disease.

This work is described in our publication Gamblin, et al., 2003a.