Reference - Detail
| RRC ID | 87594 |
|---|---|
| Author | Liew YT, Owens M, Bailey DMD, Cairns W, Day M, Jones E, McCann S, Lorenzo-Cisneros L, Murphy T, Parkin J, Tortoishell H, Dajas-Bailador F, Landgraf M, Pant DC, Voelzmann A, Prokop A. |
| Title | Loss and gain of motor protein function cause microtubule bundle damage in Drosophila axons. |
| Journal | Curr Biol |
| 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. |
| Volume | 36(3) |
| Pages | 707-722.e6 |
| Published | 2026-2-2 |
| DOI | 10.1016/j.cub.2025.12.038 |
| PII | S0960-9822(25)01691-4 |
| PMID | 41558478 |
| MeSH | Animals Axonal Transport Axons* / metabolism Axons* / physiology Drosophila Proteins* / genetics Drosophila Proteins* / metabolism Drosophila melanogaster* / genetics Drosophila melanogaster* / metabolism Drosophila melanogaster* / physiology Dyneins / genetics Dyneins / metabolism Kinesins* / genetics Kinesins* / metabolism Microtubules* / metabolism Reactive Oxygen Species / metabolism |
| IF | 9.601 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | Bluesky |
| Total number of mentions | 28 |
| Altmetric score changes over past 6months | 0.2 |
| Resource | |
| Drosophila | DGRC#150498 |