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New cell biological explanations for kinesin-linked axon degeneration

Yu-Ting Liew, View ORCID ProfileAndré Voelzmann, Liliana M. Pinho-Correia, Thomas Murphy, Haydn Tortoishell, Jill Parkin, David M.D. Bailey, View ORCID ProfileMatthias Landgraf, View ORCID ProfileAndreas Prokop
doi: https://doi.org/10.1101/2021.12.23.473961
Yu-Ting Liew
1The University of Manchester, Manchester Academic Health Science Centre, Faculty of Biology, Medicine and Health, School of Biology, Manchester, UK
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André Voelzmann
1The University of Manchester, Manchester Academic Health Science Centre, Faculty of Biology, Medicine and Health, School of Biology, Manchester, UK
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Liliana M. Pinho-Correia
1The University of Manchester, Manchester Academic Health Science Centre, Faculty of Biology, Medicine and Health, School of Biology, Manchester, UK
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Thomas Murphy
1The University of Manchester, Manchester Academic Health Science Centre, Faculty of Biology, Medicine and Health, School of Biology, Manchester, UK
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Haydn Tortoishell
1The University of Manchester, Manchester Academic Health Science Centre, Faculty of Biology, Medicine and Health, School of Biology, Manchester, UK
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Jill Parkin
1The University of Manchester, Manchester Academic Health Science Centre, Faculty of Biology, Medicine and Health, School of Biology, Manchester, UK
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David M.D. Bailey
2Department of Zoology, University of Cambridge, Downing Street, Cambridge CB2 3EJ
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Matthias Landgraf
2Department of Zoology, University of Cambridge, Downing Street, Cambridge CB2 3EJ
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Andreas Prokop
1The University of Manchester, Manchester Academic Health Science Centre, Faculty of Biology, Medicine and Health, School of Biology, Manchester, UK
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  • For correspondence: Andreas.Prokop@manchester.ac.uk
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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.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵♦ Please, note that Y.-T.L. is the key contributor to this work as part of her PhD thesis (Liew, 2018). Unfortunately, we have not been able to establish contact for over two years, so that direct consent by this author to publication of this work has not been given. However, consent is assumed from prior discussions we had.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted December 23, 2021.
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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
bioRxiv 2021.12.23.473961; doi: https://doi.org/10.1101/2021.12.23.473961
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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
bioRxiv 2021.12.23.473961; doi: https://doi.org/10.1101/2021.12.23.473961

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