A redox-dependent switch governing sensory axon degeneration and regeneration

Zebrafish (Danio rerio) fin amputation is a widely used model for studying sensory axon degeneration and regeneration. After injury, sensory neuron terminals rapidly degenerate before regenerating. While reactive oxygen species (ROS), particularly hydrogen peroxide (H₂O₂), are known to promote axon regeneration through epidermal mechanisms, their role in degeneration remains unclear. Here, we identify mitochondrial superoxide and reactive nitrogen species (RNS), specifically peroxynitrite, as key drivers of axon fragmentation. Using AlphaFold and DeepNitro predictive modeling, we identified conserved nitration and nitrosylation sites in NMNAT rather than SARM1, two key drivers of a known axon destruction pathway, suggesting the possibility of a redox-dependent regulatory mechanism. We further explored the role of NADPH in axon degeneration since cyba mutants that do not utilize NADPH to generate ROS display delayed sensory axon degeneration. Pharmacological NADPH treatment significantly reduced amputation-induced sensory axon degeneration while enhancing regeneration. NADPH co-administration also mitigated paclitaxel-induced axon loss and improved the tactile response in a model of chemotherapy-induced peripheral neuropathy. These findings reveal a complex interplay between ROS and RNS in axon degeneration and regeneration, positioning NADPH as a promising therapeutic candidate for oxidative stress-related neurodegeneration.

• Publication year

  2025

• Venue

  Scientific Reports

• Publication date

  2025-11-11

• Fields of study

  Biology, Medicine, Environmental Science

• Identifiers
  DOI 10.1038/s41598-025-23035-6PMID 41219290PMCID 12606303
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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