In agreement with the above, Cripps et al. reported that soluble paired helical filaments (PHF) of tau protein are ubiquitinylated at their microtubule-binding domain (at residues Lys-254, Lys-311, and Lys-353), suggesting that ubiquitinylation of PHF-tau may be an earlier pathological event and that ubiquitinylation could play a regulatory role in modulating the integrity of microtubules during the course of AD [84]. Here, MAPT is linked to Alzheimer disease.