Maintaining essential microtubule bundles in meter-long axons: a role for local tubulin biogenesis?

Axons are the narrow, up-to-meter long cellular processes of neurons that form the biological cables wiring our nervous system. Most axons must survive for an organism’s lifetime, i.e. up to a century in humans. Axonal maintenance depends on loose bundles of microtubules that run without interruption all along axons. The continued turn-over and the extension of microtubule bundles during developmental, regenerative or plastic growth requires the availability of α/β-tubulin heterodimers up to a meter away from the cell body. The underlying regulation in axons is poorly understood and hardly features in past and contemporary research. Here we discuss potential mechanisms, particularly focussing on the possibility of local tubulin biogenesis in axons. Current knowledge might suggest that local translation of tubulin takes place in axons, but far less is known about the post-translational machinery of tubulin biogenesis involving three chaperone complexes: prefoldin, CCT and TBC. We discuss functional understanding of these chaperones from a range of model organisms including yeast, plants, flies and mice, and explain what is known from human diseases. Microtubules across species depend on these chaperones, and they are clearly required in the nervous system. However, most chaperones display a high degree of functional pleiotropy, partly through independent functions of individual subunits outside their complexes, thus posing a challenge to experimental studies. Notably, we found hardly any studies that investigate their presence and function particularly in axons, thus highlighting an important gap in our understanding of axon biology and pathology.