The relevance of axonal swellings and atrophy to γ-diketone neurotoxicity: A forum position paper

R. M. LoPachin, E. J. Lehning

Research output: Contribution to journalReview articlepeer-review

44 Scopus citations


Traditionally, γ-diketone neuropathy is classified as a distal axonopathy and has been characterized by giant axonal swellings in CNS and PNS tissues. These swellings contain neurofilamentous masses and are associated with thinning and retraction of the myelin sheath. It has been proposed that this axonopathy is caused by direct γ-diketone modification of neurofilaments (NFs) involving pyrrolation of ε-amino groups on NF lysyl residues and possibly secondary autoxidation of the pyrrole rings with creation of covalent NF-NF crosslinks. Neurofilaments are thought to undergo chemical modification as they progress along the axonal axis and, eventually, accumulate at distal nodes of Ranvier where their proximodistal movement is impeded. Development of swelling presumably initiates axonal degeneration and subsequent functional deficits. However, other research suggests that axonal swellings are a non-specific effect related to subchronic γ-diketone exposure. Such evidence draws into question the mechanistic relevance of these swellings. In contrast, research conducted over the past decade indicates axonal atrophy is a specific morphologic component of diketone neuropathy which might have both functional and mechanistic importance. In this overview, the potential neurotoxicological significance of both axonal swellings and atrophy are evaluated critically. Based on the evidence to be presented, we propose that axonal atrophy is the morphological consequence of the molecular mechanism of γ-diketone neuropathy. Accordingly, several mechanistic scenarios related to the development of atrophy will be discussed. It is hoped that this Forum will stimulate scientific debate and initiate laboratory investigations which will either confirm or refute the involvement of axonal atrophy in γ-diketone neurotoxicity. Investigating γ- diketone atrophy might provide insight into the mechanism of other toxic axonopathies which are also associated with reduced axon caliber; e.g., acrylamide and carbon disulfide neuropathies.

Original languageEnglish (US)
Pages (from-to)7-22
Number of pages16
Issue number1
StatePublished - 1997


  • 2,5-Hexanedione
  • Axonal Atrophy
  • Axonal Swelling
  • Distal Axonopathy
  • Methyl N-butyl Ketone
  • N- hexane
  • Protein Cross- linking
  • Pyrrole Formation
  • Toxic Neuropathy
  • γ-Diketone Neuropathy

ASJC Scopus subject areas

  • General Neuroscience
  • Toxicology


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