Oxidative stress promotes axonal atrophy through alterations in microtubules and EB1 function DOI
Samuel Shields,

Oliver R. Wilkes,

Illana Gozes

и другие.

Опубликована: Июль 12, 2024

Abstract Axons are crucial for transmitting neurochemical signals. As organisms age, the ability of neurons to maintain their axons declines; hence aged more susceptible damage or dysfunction. Understanding what causes axonal vulnerability is developing strategies enhance overall resilience neurons, and prevent deterioration during ageing in age-related neurodegenerative diseases. Increasing levels reactive oxygen species (ROS) oxidative stress, a hallmark Despite this association, causal relationship between stress neuronal remains unclear, particularly how subcellular physiology affected by ROS. By using Drosophila -derived primary cultures recently developed vivo model ageing, which involves visualisation medulla we investigated interplay microtubule cytoskeleton. We find that as key driver synaptic decay, including appearance swellings, alterations both synapses morphological transformation terminals ageing. demonstrate increased ROS sensitises plus end binding factor, end-binding protein 1 (EB1), leading defects, affecting integrity. Furthermore, manipulating EB1 proved be valuable therapeutic strategy hallmarks observed conditions elevated In summary, mechanistic pathway linking cellular cytoskeleton provide evidence potential enhancing improve axons.

Язык: Английский

Oxidative Stress Promotes Axonal Atrophy through Alterations in Microtubules and EB1 Function DOI Creative Commons
Samuel Shields,

Emilia Gregory,

Oliver R. Wilkes

и другие.

Aging and Disease, Год журнала: 2025, Номер unknown, С. 0 - 0

Опубликована: Янв. 1, 2025

Axons are crucial for transmitting neurochemical signals. As organisms age, the ability of neurons to maintain their axons declines; hence, aged more susceptible damage or dysfunction. Understanding how aging causes axonal vulnerability is developing strategies enhance overall resilience and prevent neuronal deterioration during in age-related neurodegenerative diseases. Increasing levels reactive oxygen species (ROS) oxidative stress - a hallmark Despite this association, causal relationship between remains unclear, particularly subcellular physiology may be affected by ROS. By using Drosophila-derived primary cultures recently developed vivo model aging, which involves visualisation Drosophila medulla neurons, we investigated interplay stress, microtubule cytoskeleton. Our results showed that key driver synaptic decay, as shown an enhanced appearance swellings, alterations (in both synapses) morphological transformation terminals aging. We demonstrated increasing ROS sensitises plus end-binding protein 1 (EB1), leading defects effect integrity. Furthermore, manipulating EB1 proved valuable therapeutic strategy hallmarks conditions elevated In summary, demonstrate mechanistic pathway linking cellular with changes cytoskeleton provide evidence potential enhancing plus-end improve axons.

Язык: Английский

Процитировано

1
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

Процитировано

0
Microtubule acetylation is a biomarker of cytoplasmic health during cellular senescence DOI Creative Commons
Yusheng Shen, Roilea Maxson, Richard J. McKenney

и другие.

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

Опубликована: Апрель 1, 2025

Cellular senescence is marked by cytoskeletal dysfunction, yet the role of microtubule post-translational modifications (PTMs) remains unclear. We demonstrate that acetylation increases during drug-induced in human cells and natural aging Drosophila . Elevating via HDAC6 inhibition or α TAT1 overexpression BEAS-2B disrupts anterograde Rab6A vesicle transport, but spares retrograde transport Rab5 endosomes. Hyperacetylation results slowed polymerization decreased cytoplasmic fluidity, impeding diffusion micron-sized condensates. These effects are distinct from enhanced detyrosination, correlate with altered viscoelasticity resistance to osmotic stress. Modulating viscosity reciprocally perturbs dynamics, revealing bidirectional mechanical regulation. Senescent phenocopy hyperacetylated cells, exhibiting analogous on polymerization. Our findings establish as a biomarker for health potential driver age-related densification organelle decline, linking PTMs biomechanical feedback loops exacerbate senescence. This work highlights bridging changes broader hallmarks.

Язык: Английский

Процитировано

0
Redox signaling modulates axonal microtubule organization and induces a specific phosphorylation signature of microtubule-regulating proteins DOI Creative Commons
Christian Conze, Nataliya I. Trushina, Nanci Monteiro-Abreu

и другие.

Redox Biology, Год журнала: 2025, Номер unknown, С. 103626 - 103626

Опубликована: Апрель 1, 2025

Many life processes are regulated by physiological redox signaling, but excessive oxidative stress can damage biomolecules and contribute to disease. Neuronal microtubules critically involved in axon homeostasis, regulation of axonal transport, neurodegenerative processes. However, whether how signaling affects is largely unknown. Using live cell imaging super-resolution microscopy, we show that subtoxic concentrations the central metabolite hydrogen peroxide increase microtubule dynamics, alter structure array, affect efficiency transport. We report mitochondria-targeting antioxidant SkQ1 stabilizer EpoD abolish dynamics. found specifically modulates phosphorylation state microtubule-regulating proteins, which differs from arsenite as an alternative inducer, induces a non-overlapping pattern MAP1B main target. Cell-wide phosphoproteome analysis revealed pathways inversely activated arsenite. In particular, treatment was associated with kinases suppress apoptosis regulate brain metabolism (PRKDC, CK2, PDKs), suggesting these play role modulation organization. The results suggest second messenger rapid local reorganization array response mitochondrial activity or neighboring cells activating specific cascades.

Язык: Английский

Процитировано

0
SENESCENT CELLS AND THEIR IMPORTANCE IN HISTOGENESIS DOI
R. V Deev, Yuliya V. Markina, Tatiana V. Kirichenko

и другие.

Morphology, Год журнала: 2025, Номер unknown

Опубликована: Апрель 11, 2025

Cellular senescence is currently one of the dominant concepts aging. Some cells in developing tissues (prenatal histogenesis) and definitive acquire morphofunctional changes associated with an increase size, formation special areas heterochromatin, a secretory phenotype production proinflammatory cytokines, β-galactosidase, TGFβ, etc. combination blocking mitosis due to active transcription р16INK4A, p21CIP1. It assumed that such cells, called senescent, are not transitional form histogenesis from actively functioning component differon dying by programmed types cell death, but separate functional stage cytogenesis. The histogenetic significance physiological reparative regeneration various tissues, as well their effect on histophysiology, requires further study. Pharmacological elimination senescent section anti-aging therapy.

Язык: Английский

Процитировано

0
Oxidative stress promotes axonal atrophy through alterations in microtubules and EB1 function DOI
Samuel Shields,

Oliver R. Wilkes,

Illana Gozes

и другие.

Опубликована: Июль 12, 2024

Abstract Axons are crucial for transmitting neurochemical signals. As organisms age, the ability of neurons to maintain their axons declines; hence aged more susceptible damage or dysfunction. Understanding what causes axonal vulnerability is developing strategies enhance overall resilience neurons, and prevent deterioration during ageing in age-related neurodegenerative diseases. Increasing levels reactive oxygen species (ROS) oxidative stress, a hallmark Despite this association, causal relationship between stress neuronal remains unclear, particularly how subcellular physiology affected by ROS. By using Drosophila -derived primary cultures recently developed vivo model ageing, which involves visualisation medulla we investigated interplay microtubule cytoskeleton. We find that as key driver synaptic decay, including appearance swellings, alterations both synapses morphological transformation terminals ageing. demonstrate increased ROS sensitises plus end binding factor, end-binding protein 1 (EB1), leading defects, affecting integrity. Furthermore, manipulating EB1 proved be valuable therapeutic strategy hallmarks observed conditions elevated In summary, mechanistic pathway linking cellular cytoskeleton provide evidence potential enhancing improve axons.

Язык: Английский

Процитировано

1