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

• Published in: Current biology 2018-07, Vol.28 (13), p.2181-2189.e4
• Main Authors: Qiang, Liang, Sun, Xiaohuan, Austin, Timothy O., Muralidharan, Hemalatha, Jean, Daphney C., Liu, Mei, Yu, Wenqian, Baas, Peter W.
• Format: Article
• Language: English
• Subjects: axon; MAP6; microtubule; microtubule stability; neuron; tau
• ISSN: 0960-9822; 1879-0445
• DOI: 10.1016/j.cub.2018.05.045

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. [Display omitted] •Rat neurons depleted of tau display loss of labile microtubule mass from the axon•Tau depletion leads to a broader distribution of MAP6 on axonal microtubules•Tau is not a stabilizer of axonal microtubules•Tau’s role in the axon is to allow microtubules to have long labile domains Qiang, Sun, et al. show that cultured rat neurons depleted of tau undergo microtubule loss that is not explicable on the basis of microtubule destabilization. Rather, the loss is due to the diminution of the labile domains of microtubules, indicating that tau’s actual role in the axon is to allow microtubules to have long labile domains.