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Loss and gain of motor protein function cause microtubule bundle damage in Drosophila axons.

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Affiliations

  • 1. The University of Manchester, Manchester Academic Health Science Centre, Faculty of Biology, Medicine and Health, School of Biology, Manchester M13 9PT, UK.
      Authors
    • Liew YT 1
    • Owens M 1
    • Cairns W 1
    • Day M 1
    • Jones E 1
    • Lorenzo-Cisneros L 1
    • Murphy T 1
    • Parkin J 1
    • Tortoishell H 1
    • Prokop A 1
    (10 authors)
  • 2. Department of Zoology, University of Cambridge, Downing Street, Cambridge CB2 3EJ, UK.
      Authors
    • Bailey DMD 2
    • Landgraf M 2
    (2 authors)
  • 3. School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, UK.
      Authors
    • McCann S 3
    • Dajas-Bailador F 3
    (2 authors)
  • 4. Department of Cell Biology, Emory University, Atlanta, GA 30322, USA.
      Authors
    • Pant DC 4
    (1 author)
  • 5. The University of Manchester, Manchester Academic Health Science Centre, Faculty of Biology, Medicine and Health, School of Biology, Manchester M13 9PT, UK; School of Environmental and Life Sciences, Faculty of Science and Engineering, University of Hull, Hull HU6 7RX, UK.
      Authors
    • Voelzmann A 5
    (1 author)

Current Biology : CB, 19 Jan 2026, :S0960-9822(25)01691-4
https://doi.org/10.1016/j.cub.2025.12.038 PMID: 41558478 

Abstract 

Neurodegeneration often starts by atrophy of the cable-like nerve fibers (axons) that wire nervous systems. Maintaining axons requires supply via motor-protein-driven transport along uninterrupted bundles of microtubules. Functional loss of motor proteins, but surprisingly also their hyperactivation, links to conditions of axonal atrophy; in both cases the underlying mechanisms are little understood. To bridge this important knowledge gap, we carried out systematic studies using 40 different genetic tools to manipulate 19 context-related genes in one standardized Drosophila primary neuron system. Starting with transport motors, we found that downregulation in at least three of them-dynein heavy chain, the kinesin family member 5 (KIF5) ortholog kinesin heavy chain (Khc), and KIF1A ortholog Unc-104-caused disintegration of axonal microtubule bundles, which we refer to as "microtubule-curling"; this damages the essential highways for life-sustaining axonal transport. To understand this phenomenon, we focused on Khc's various subfunctions. We found that abolishing Khc-mediated mitochondrial and lysosomal transport affects the homeostasis of reactive oxygen species (ROS), which in turn triggers microtubule-curling in fly and mouse neurons alike. Taking the opposite approach by using conditions where Khc is hyperactive, we observed comparable microtubule-curling, triggered by an ROS-independent mechanism likely involving excessive mechanical force generation. To assess wider relevance of our findings, we studied Unc-104, its binding partner KIF-binding protein (KIFBP), and human KIF5A. These studies suggest that functional loss and hyperactivation of other transport motors also cause ROS-dependent and -independent microtubule-curling, which could therefore represent two fundamental pathways that link transport motors to microtubule bundle decay and neurodegeneration.

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Read article at publisher's site: https://doi.org/10.1016/j.cub.2025.12.038

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    Funding 

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    Biotechnology and Biological Sciences Research Council (7)

    • Grant ID: BB/R016666/1

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    • Grant ID: BB/T0083690/1

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    • Grant ID: BB/M007553/1

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    • Grant ID: BB/I002448/1

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    • Grant ID: BB/P020151/1

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    • Grant ID: BB/T008725/1

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    • Grant ID: BB/L000717/1

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    Muscular Dystrophy Association (1)

    • Grant ID: 1052778

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    National Institutes of Health (1)

    • Grant ID: P40OD018537

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    University of Manchester

      Wellcome Trust (1)

      • Grant ID: 087742/Z/08/Z

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