Tau oligomerization on microtubules in health and disease

Abstract

When it comes to the microtubule-associated protein (MAP), tau, an internet search or a typical review article reveals a central dogma about its role in human disease.The dogma generally states that under physiological conditions, tau binds along the microtubule lattice, providing stability to the polymerized microtubule structure 1 .However, in disease, hyperphosphorylation (~3-4 fold increase in phosphorylated residues 2,3 ) of tau results in its dissociation from microtubules, causing destabilization and subsequent loss of microtubules within diseased neurons.Subsequently, the dissociated hyperphosphorylated tau selfassociates into filamentous aggregates that are the hallmarks of advanced tauopathies and neurodegeneration 1 .Early work showed that tau alters the parameters of microtubule dynamic instability, reducing catastrophes and slowing depolymerization rates, implying tau acts to stabilize microtubules 4,5 .Additionally, microtubule density within axons of tau knockout mice appeared lower.However, the magnitude of this effect was variable between mouse lines (~12-40%), and limited to the proximal regions of only small caliber axons 6 .Microtubule density in dendrites was not affected by loss of tau.Nonetheless, the prevailing notion of tau as a microtubule stabilizer in neurons has been widely accepted in the literature.However, it is important to stress that tau binding does not abolish dynamic instability.In addition, subsequent studies have challenged this dogma, revealing that tau is not the potent stabilizer it was once thought to be 7,8 .We note here that the definition of "stabilize" may not be uniform in the literature, but the term is typically taken as counteracting the loss of total microtubule mass in neurons.In this respect, the definition of tau as a 'stabilizer' of microtubules would mean that the failure of tau activity would result in the overall loss of microtubule polymer within cells.It is worth noting that neurons contain many other MAPs that interact with, and stabilize or alter, microtubule dynamics, raising further questions about why the specific loss of tau would lead to overall microtubule destabilization in cells 9 .While this topic has been comprehensively reviewed elsewhere 1 , it raises a crucial question: if the primary function of tau is not to stabilize microtubules, then what is it?From a microtubule biologist's perspective, in order to understand the conversion of tau to its pathological state, one must first understand the normal physiological behaviors of the molecule on microtubules.Here, we review our recent work on the behaviors of tau on microtubules and the potential roles it may play in neurons.We also speculate as to how these processes may go awry when tau forms pathological oligomers.