Role of tau in the spatial organization of axonal microtubules: keeping parallel microtubules evenly distributed despite macromolecular crowding

Abstract

Opposing views have been proposed regarding the role of tau, the principal microtubule-associated protein in axons. On the one hand, tau forms cross-bridges at the interface between microtubules and induces microtubule bundling in neurons. On the other hand, tau is also considered a polymer brush which efficiently separates microtubules. In mature axons, microtubules are indeed arranged in parallel arrays and are well separated from each other. To reconcile these views, we developed a mechanistic model based on in vitro and cellular approaches combined to analytical and numerical analyses. The results indicate that tau forms long-range cross-bridges between microtubules under macromolecular crowding conditions. Tau cross-bridges prevent the redistribution of tau away from the interface between microtubules, which would have occurred in the polymer brush model. Consequently, the short-range attractive force between microtubules induced by macromolecular crowding is avoided and thus microtubules remain well separated from each other. Interestingly, in this unified model, tau diffusion on microtubules enables to keep microtubules evenly distributed in axonal sections at low tau levels.Electronic supplementary materialThe online version of this article (doi:10.1007/s00018-016-2216-z) contains supplementary material, which is available to authorized users.

Local nucleation of microtubule bundles through tubulin concentration into a condensed tau phase

“…S5C and movie 9). This is consistent with recent work showing that tau binds to microtubules through its microtubule binding domains, while the intrinsically disordered N-terminal domain acts as a brush, which keep microtubules at a constant distance in microtubule bundles (Chung et al, 2016;Marx et al, 2000;Méphon-Gaspard et al, 2016;Mukhopadhyay and Hoh, 2001;Mukhopadhyay et al, 2004).…”

Microtubules as platforms for probing liquid–liquid phase separation in cells – application to RNA-binding proteins

“…Time-lapse imaging further reveals the presence of dynamical TDP-43 compartments that move along microtubules, and appear and disappear ( ). The mobility of tau on microtubules ( Janning et al, 2014 ; Méphon-Gaspard et al, 2016 ) most probably partly preserves compartment dynamics. To decipher whether RBPs account for the spatial segregation observed, we analyzed the spatial segregation of tau–RFP and either tau–GFP or tau–GFP–TDP-43 in HeLa cells co-expressing two protein fusions.…”

Tau and Axonal Transport Misregulation in Tauopathies

“…Tau may also alter FAT through direct effects on microtubule organization. Tau, in an isoform-specific manner, may act as a microtubule-spacer that simultaneously bundles microtubules and prevents them from overcrowding which could facilitate transport under normal cellular conditions [58]. Microtubule-based effects were also examined by overexpressing or deleting the fly homologue of human tau in Drosophila melanogaster neurons [91].…”