The model of local axon homeostasis - explaining the role and regulation of microtubule bundles in axon maintenance and pathology

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Axons are the slender, cable-like, up to meter-long projections of neurons that electrically wire our brain and body. In spite of their challenging morphology, they usually need to be maintained for an organism's lifetime. This makes them key lesion sites in pathological processes of ageing, injury and neurodegeneration. To better understand how axons are formed and maintained long-term, we focus here on the parallel bundles of microtubules (MTs) which form their indispensable structural backbones and highways for life-sustaining cargo transport and organelle dynamics. Many MT-binding and -regulating proteins in axons have prominent hereditary links to axon degeneration, but knowing their molecular roles is usually insufficient to explain their roles during axon morphogenesis, maintenance or pathology. Such understanding requires deciphering how these proteins interact in regulatory networks to implement observed cellular phenomena. Here we propose the model of local axon homeostasis as a conceptual framework that attempts to combine current knowledge into one coherent interactome. According to this model, each area of an axon is self-sustaining through local auto-regulatory networks; these networks maintain a balance between (1) the enormous mechanical challenges posed by the life-sustaining intra-axonal motor dynamics and (2) the maintenance activities required to sustain MT bundles as the highways needed for those dynamics. This model offers a new level of explanation, and we hope that it will help to raise the interest in axonal MTs and lead to the generation of more data that can help to decipher the important contributions of MTs to axon biology and pathology.

Bibliographical metadata

Original languageEnglish
Article number10.1101/577320
Publication statusPublished - 15 Mar 2019