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

Yu-Ting Liew,

André Voelzmann,

Michael J. Owens

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

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

Язык: Английский

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

Yu-Ting Liew,

André Voelzmann,

Michael J. Owens

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

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

Язык: Английский

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