Post-translational modifications of tau protein

Abstract

Microtubule-associated protein tau is a phosphoprotein whose expression and phosphorylation is developmentally regulated. Whereas in adult mammalian brain several isoforms are produced from a single gene by alternative splicing, in fetal brain only a single isoform exists, corresponding to the smallest of the tau isoforms. Main physiological function of tau is the promotion of assembly and stabilization of microtubular network, which is essential for normal axonal transport of vesicles within the neuron. In human, tau protein undergoes several posttranslational modifications: such as phosphorylation, truncation, nitration, glycation, glycosylation, ubiquitination and polyaminations. When these modifications are disturbed, they play a serious role during the pathogenesis of Alzheimer's disease (AD). Hyperphosphorylation and truncation as the early events in AD pathogenesis, play significant role in the formation of neurofibrillary pathology. Phosphorylated tau has reduced capability in binding to microtubules and hyperphosphorylation together with truncation contributes to the formation of pathological tau filaments. This leads to destabilization of microtubular network and subsequent impairment of microtubule associated axonal transport. Since many data suggest that sporadic AD is the "disease of posttranslational modifications" of tau protein, more detailed investigation of tau protein modifications is urgently needed in order to understand pathogenesis of sporadic Alzheimer's disease (Fig. 1, Ref. 86).