Microtubules, major components of the cytoskeleton, are 25 nm-wide hollow tubes composed of tubulin dimers. Microtubules are dynamic structures: they spontaneously alternate between phases of assembly and disassembly through gain and loss of tubulin dimers at their extremities. This unique property known as dynamic instability is crucial for cell plasticity and cellular events such as cell division and motility. In terminally differentiated cells such as neurons, dynamic microtubules co-exist with stable microtubules that exhibit a low turnover of tubulin and are resistant to external stresses like bending forces or load. Stable microtubules are crucial to maintain neuronal specific morphology and to accommodate morphological changes responsible for neuronal development and activity. In pathological conditions such as neurodegenerative diseases or brain injury, abnormal microtubule stability leads to an imbalance between dynamic and stable microtubule populations. To date, the molecular basis behind the stability of neuronal microtubules remain mysterious. Strikingly, protein densities called MIPs (Microtubule Inner Proteins) have been observed for a long time inside neuronal microtubules and proposed to confer neuronal microtubules their high stability. However, the molecular identity of these neuronal MIPs remained totally unknown until today.

In that context, a collaborative work between Annie Andrieux’s and Isabelle Arnal’s teams recently allowed identifying MAP6 as the first neuronal MIP in mammals. MAP6 is a neuronal protein that stabilizes microtubules. MAP6-deficient mice suffer from severe cognitive and behavioral deficits related to schizophrenia, deficits due at least in part to an alteration in microtubule stability. The two teams have discovered that MAP6 can localize in the lumen of microtubules. MAP6 inside microtubules generates microtubules with remarkable properties including a helical growth and the formation of persistent holes in the lattice. What could be the role of such helical microtubules with persistent holes? One possibility is that apertures could facilitate the accessibility of other proteins to the lumen, for instance the enzyme aTAT1 known to acetylate the microtubule inner face, a modification associated with mechanical resistance of microtubules. The helical structure of microtubules generated by MAP6 exhibit a width equivalent to that of axons: they could therefore define the diameter of axons and/or confer to axons physical resistance to the compressive forces they encounter in brain tissues during development or regeneration.

This pioneering discovery of the first MIP present in the lumen of neuronal microtubules opens up a completely new field of investigation to understand this hidden side of microtubules. Exploring the inner life of neuronal microtubules, hitherto unknown, should reveal new functions of these biopolymers.


The neuronal protein MAP6 localizes inside microtubules (cryo-electron tomography) and induces their helical growth (Total Internal Reflection Fluorescence microscopy).
© Christophe Bosc, Camille Cuveillier and Julie Delaroche.