Tau can undergo a variety of post-translational modifications including phosphorylation, acetylation, methylation, ubiquitylation, SUMOylation, glycation, glycosylation, nitration, and truncation. There are over 90 identified phosphorylation sites alone, and a host of putative sites for additional modifications. These PTMs can take place in all 6 isoforms of tau found in the brain and the possible combinations in one particular molecule of tau are nearly infinite. It is therefore extremely difficult to determine if and which PTMs are responsible for tau toxicity. The overall hypothesis has been that PTMs, phosphorylation in particular, interfere with tau–microtubule binding thereby enhancing the propensity of tau to misfold and aggregate. The availability of phospho-tau antibodies and the correlation between increased tau phosphorylation and disease progression gave rise to the hypothesis that phosphorylation plays a critical role in tau pathophysiology.
