Tau Does Not Stabilize Axonal Microtubules but Rather Enables Them to Have Long Labile Domains

Abstract

It is widely believed that tau stabilizes microtubules in the axon [1-3] and, hence, that disease-induced loss of tau from axonal microtubules leads to their destabilization [3-5]. An individual microtubule in the axon has a stable domain and a labile domain [6-8]. We found that tau is more abundant on the labile domain, which is inconsistent with tau's proposed role as a microtubule stabilizer. When tau is experimentally depleted from cultured rat neurons, the labile microtubule mass of the axon drops considerably, the remaining labile microtubule mass becomes less labile, and the stable microtubule mass increases. MAP6 (also called stable tubule-only polypeptide), which is normally enriched on the stable domain [9], acquires a broader distribution across the microtubule when tau is depleted, providing a potential explanation for the increase in stable microtubule mass. When MAP6 is depleted, the labile microtubule mass becomes even more labile, indicating that, unlike tau, MAP6 is a genuine stabilizer of axonal microtubules. We conclude that tau is not a stabilizer of axonal microtubules but is enriched on the labile domain of the microtubule to promote its assembly while limiting the binding to it of genuine stabilizers, such as MAP6. This enables the labile domain to achieve great lengths without being stabilized. These conclusions are contrary to tau dogma.

Elucidating Tau function and dysfunction in the era of cryo-EM

“…Beyond proving that the turn conformation is possible, the combined structures hence provide an additional link between Tau's functional and pathological conformations, in line with previous studies that hint at a role for tubulin in the aggregation process. Whether in vivo aggregation of Tau occurs at the microtubule surface (78,79) or rather through the soluble tubulin (80) remains unclear but could be related to the recent controversy whether Tau stabilizes MTs or enables these same axonal MTs to have labile domains (81,82).…”

Acetylation changes tau interactome to degrade tau in Alzheimer’s disease animal and organoid models

“…Intracellular accumulation of pathological tau proteins as neurofibrillary tangles (NFTs) and extracellular accumulation of beta‐amyloid (Aβ) as senile plaques are the major pathological features of AD (Querfurth & LaFerla, ). Physiologically, tau regulates microtubule dynamics (Qiang et al, ), whereas pathologically, tau is highly phosphorylated and aggregates to form NFTs in AD (Wang & Mandelkow, ). Hyperphosphorylated and aggregated tau leads to synapse dysfunction, mitochondrial damage, and neuronal cell death (Shafiei, Guerrero‐Munoz, & Castillo‐Carranza, ; Wang & Mandelkow, ).…”

Improving Mouse Models for Dementia. Are All the Effects in Tau Mouse Models Due to Overexpression?

“…Tau is a microtubule-binding protein that is thought to stabilize (Gong and Iqbal 2008) or at least promote assembly of microtubules (Qiang et al 2018). Tau has also been implicated in the transport of proteins along the axon by competing with binding of kinesin and dynein to the microtubules (Dixit et al 2008).…”