Different mechanisms link gain and loss of kinesin functions to axonal degeneration

Liew Yu-Ting, André Voelzmann, Milli Owens, Maureece Day, Will Cairns, Ella Jones, Federico Dajas-bailador, Sophie McCann, Thomas Murphy, Haydn Tortoishell, Jill Parkin, David M. D. Bailey, Matthias Landgraf, Andreas Prokop

Research output: Preprint/Working paperPreprint

Abstract

Axons are the slender, often 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. Long-term maintenance and sustained functionality of axons requires motor protein-driven transport distributing life-sustaining materials and organelles to places of need. It seems therefore plausible that loss of motor function can cause axon degeneration; however, also gain-of-function conditions were linked to disorders including motor neuron disease or spastic paraplegia. To understand this phenomenon, we studied ~40 genetic manipulations of motor proteins, cargo linkers and regulators of reactive oxygen species in one standardised Drosophila primary neuron system. Using axonal microtubule bundle organisation as a relevant readout reflecting the state of axon integrity, we found that losses of Dynein heavy chain, KIF1A/Unc-104 and KIF5/Kinesin heavy chain (Khc) all cause bundle disintegration in the form of chaotically curled microtubules. Detailed functional studies of Khc and its adaptor proteins revealed that losses of mitochondrial or lysosomal transport cause ROS dyshomeostasis, which is a condition that inducing MT-curling in fly and mouse neurons alike. We find that hyper-activated Khc induces the same MT-curling phenotype, not through ROS but directly through enhanced mechanical forces. Studies with loss of Unc-104 and expression of an ALS-linked mutant form of the human Khc orthologue KIF5A suggest that the two mechanisms apply to motors beyond Khc. We discuss a model which can explain the surprising common outcome of both conditions and examine its relevance for understanding motor-linked neurodegeneration.
Original languageEnglish
PublisherCold Spring Harbor Laboratory Press
Publication statusPublished - 1 Jan 2025

Publication series

NamebioRxiv
PublisherCold Spring Harbor Laboratory Press
ISSN (Print)2692-8205

Keywords

  • kinesin
  • neurodegeneration
  • microtubues
  • Drosphila
  • axons
  • motor proteins

Fingerprint

Dive into the research topics of 'Different mechanisms link gain and loss of kinesin functions to axonal degeneration'. Together they form a unique fingerprint.

Cite this