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Programmed axon degeneration: mechanism, inhibition and therapeutic potential

Andrea Loreto1,2,3, Lukas J Neukomm4

  • 1Neuroscience, School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.

Nature Reviews. Neuroscience
|November 12, 2025
PubMed

Insights

Programmed axon degeneration (PAxD) triggers self-destruction of severed axons and can be targeted for neurodegenerative disease therapies. Understanding its NAD+ metabolism and Ca2+ signaling is key to developing new treatments for axonopathies.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cell Biology

Background:

  • Programmed axon degeneration (PAxD) is a conserved process for eliminating damaged or severed axons.
  • PAxD can be triggered by both axonal injury and other insults, leading to axon loss.
  • It represents a potential therapeutic target for neurological disorders.

Purpose of the Study:

  • To review the molecular mechanisms underlying PAxD.
  • To explore the role of nicotinamide adenine dinucleotide (NAD+) metabolism and Ca2+ signaling in PAxD.
  • To discuss the therapeutic potential of inhibiting PAxD in human diseases and axonopathies.

Main Methods:

  • Literature review of PAxD mechanisms.
  • Analysis of NAD+ metabolism and Ca2+ signaling pathways in axon degeneration.
  • Examination of PAxD's role in various non-axotomy disease models.

Main Results:

  • PAxD involves regulated self-destruction of axons, distinct from necrosis.
  • Nicotinamide adenine dinucleotide (NAD+) levels and Ca2+ dynamics are critical regulators of PAxD.
  • PAxD contributes to axon loss in several human neurological conditions.

Conclusions:

  • Inhibiting PAxD is a promising therapeutic strategy for axonopathies.
  • Further research into PAxD mechanisms and biomarkers is needed for clinical translation.
  • Targeting PAxD holds potential for treating a range of neurological diseases.

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