| RRC ID |
87594
|
| 著者 |
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.
|
| タイトル |
Loss and gain of motor protein function cause microtubule bundle damage in Drosophila axons.
|
| ジャーナル |
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.
|
| 巻・号 |
36(3)
|
| ページ |
707-722.e6
|
| 公開日 |
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
|
| リソース情報 |
| ショウジョウバエ |
DGRC#150498 |
