Vulnerabilities in the Tau Network and the Role of Ultrasensitive Points in Tau Pathophysiology
The network captures tau phosphorylation and dephosphorylation, microtubule binding and release, uptake, rescue, and degradation by the chaperone machinery, and aggregation. Specifically, unphosphorylated tau (Tau0) can be degraded or phosphorylated, producing normally phosphorylated tau (TauN). TauN can also be degraded in a non-ubiquitin dependent fashion, dephosphorylated, or phosphorylated to create abnormal tau (TauH), which can likewise be degraded, dephosphorylated, or phosphorylated. Each of these free tau species undergoes a conformation change to produce a form with high affinity for microtubules; these species are denoted with a star as Tau0*, TauN*, and TauH*. Abnormal TauH is taken up by the chaperone Hsp70, which mediates the decision between rescue and degradation. Both isoforms participate in the same series of reactions, but at different rates of reaction, and their behavior is coupled through the chaperone and degradation machinery.