New cell biological explanations for kinesin-linked axon degeneration

Yu-Ting Liew, André Voelzmann, Liliana M. Pinho-Correia, Thomas Murphy, Haydn Tortoishell, Jill Parkin, David M.D. Bailey, Matthias Landgraf, Andreas Prokop

Research output: Working paperPreprint

Abstract

Axons are the slender, up to meter-long projections of neurons that form the biological cables wiring our bodies. Most of these delicate structures must survive for an organism's lifetime, meaning up to a century in humans. Axon maintenance requires life-sustaining motor protein-driven transport distributing materials and organelles from the distant cell body. It seems logic that impairing this transport causes systemic deprivation linking to axon degeneration. But the key steps underlying these pathological processes are little understood. To investigate mechanisms triggered by motor protein aberrations, we studied more than 40 loss- and gain-of-function conditions of motor proteins, cargo linkers or further genes involved in related processes of cellular physiology. We used one standardised Drosophila primary neuron system and focussed on the organisation of axonal microtubule bundles as an easy to assess readout reflecting axon integrity. We found that bundle disintegration into curled microtubules is caused by the losses of Dynein heavy chain and the Kif1 and Kif5 homologues Unc-104 and Kinesin heavy chain (Khc). Using point mutations of Khc and functional loss of its linker proteins, we studied which of Khc's sub-functions might link to microtubule curling. One cause was emergence of harmful reactive oxygen species through loss of Milton/Miro-mediated mitochondrial transport. In contrast, loss of the Kinesin light chain linker caused microtubule curling through an entirely different mechanism appearing to involve increased mechanical challenge to microtubule bundles through de-inhibition of Khc. The wider implications of our findings for the understanding of axon maintenance and pathology are discussed.
Original languageEnglish
PublisherbioRxiv
DOIs
Publication statusPublished - 23 Dec 2021

Keywords

  • axonal transport
  • axons
  • neurodegeneration
  • microtubules
  • motor proteins
  • kinesins
  • mitochondria
  • synapses

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