Abstract
Programmed axon degeneration (PAxD) is an evolutionarily conserved mechanism in the nervous system that is activated by axonal injury (axotomy) to execute the self-destruction of a severed distal axon. It can also be triggered by non-axotomy insults, resulting in the loss of axons connected to their cell bodies. PAxD is therefore a promising target for therapeutic intervention and drugs that inhibit it are currently being tested in clinical trials. In this Review, we summarize the molecular mechanism of PAxD, focusing on its regulation by nicotinamide adenine dinucleotide (NAD+) metabolism and how it dictates Ca2+-mediated axonal demise. We examine its involvement in human disease and its potential as a therapeutic target by dissecting its role in various non-axotomy disease models. Finally, we address key challenges for its clinical translation, including the need for relevant biomarkers and safety considerations. Further advancements in understanding PAxD will pave the way for new therapeutic strategies targeting human axonopathies.
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Acknowledgements
The authors thank A. DiAntonio, A. Höke, B. Kobe, G. Orsomando, J. Gilley, M. Coleman and Y. Sasaki for their constructive feedback on the manuscript. A.L. is supported by the Faculty of Medicine and Health and Save Sight Institute New Academic Staff Funding (University of Sydney) and the Snow Vision Accelerator (Snow Medical). L.J.N. is supported by two Swiss National Science Foundation (SNSF) Assistant Professor starting grants (PP00P3_176855 and PP00P3_211015), a SNSF project grant (320030-236186) and the University of Lausanne/Canton de Vaud.
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Glossary
- Antisense oligonucleotides
-
Short synthetic strands of DNA or RNA designed to bind to specific target RNA molecules to block the RNA from producing a protein, altering its normal function or stability.
- Axonopathies
-
Neurological disorders characterized by progressive axonal degeneration, leading to disrupted neuronal communication.
- Base-exchange activity
-
The ability of an enzyme to swap one base for another within a larger molecule, often a nicotinamide adenine dinucleotide (NAD+)-related (or phospholipid) compound.
- Base-exchange inhibitors
-
(BEIs). They work as a base within the catalytic site of sterile-α and TIR motif-containing protein 1 (SARM1) by replacing nicotinamide in the NAD+ substrate to form a stable base–adenosine diphosphate-ribose adduct, thereby blocking SARM1 NADase activity.
- Glycohydrolase
-
An enzyme that breaks glycosidic bonds — using either water (hydrolysis) or alternative nucleophiles — thereby degrading complex substrates into simpler components.
- Passenger mutations
-
In the context of genetically modified organisms, passenger mutations are unintended genetic differences from a donor’s genetic background that are inadvertently transferred to a recipient during the genetic engineering process, potentially causing experimental bias or an unexpected phenotype.
- Phase transition
-
Reversible or irreversible changes in the physical state of proteins from liquid-like condensates into solid aggregates altering organization and function.
- Transglycosidase
-
An enzyme whose activity transfers a glycosyl (sugar) group from one molecule to another rather than hydrolysing it.
- Wallerian degeneration
-
The process of axotomy-induced distal axon degeneration and the clearance of the resulting debris by surrounding glia and immune cells, named after August Waller.
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Loreto, A., Neukomm, L.J. Programmed axon degeneration: mechanism, inhibition and therapeutic potential. Nat. Rev. Neurosci. 27, 44–60 (2026). https://doi.org/10.1038/s41583-025-00986-3
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DOI: https://doi.org/10.1038/s41583-025-00986-3
