Axonopathy is a compounding factor in the pathogenesis of Krabbe disease

Acta Neuropathol. 2011 Jul;122(1):35-48. doi: 10.1007/s00401-011-0814-2. Epub 2011 Mar 4.


Loss-of-function of the lysosomal enzyme galactosyl-ceramidase causes the accumulation of the lipid raft-associated sphingolipid psychosine, the disruption of postnatal myelination, neurodegeneration and early death in most cases of infantile Krabbe disease. This work presents a first study towards understanding the progression of axonal defects in this disease using the Twitcher mutant mouse. Axonal swellings were detected in axons within the mutant spinal cord as early as 1 week after birth. As the disease progressed, more axonopathic profiles were found in other regions of the nervous system, including peripheral nerves and various brain areas. Isolated mutant neurons recapitulated axonal and neuronal defects in the absence of mutant myelinating glia, suggesting an autonomous neuronal defect. Psychosine was sufficient to induce axonal defects and cell death in cultures of acutely isolated neurons. Interestingly, axonopathy in young Twitcher mice occurred in the absence of demyelination and of neuronal apoptosis. Neuronal damage occurred at later stages, when mutant mice were moribund and demyelinated. Altogether, these findings suggest a progressive dying-back neuronal dysfunction in Twitcher mutants.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Axons / drug effects
  • Axons / pathology*
  • Cells, Cultured
  • Demyelinating Diseases / pathology
  • Disease Models, Animal
  • Disease Progression*
  • Leukodystrophy, Globoid Cell / etiology*
  • Leukodystrophy, Globoid Cell / pathology
  • Leukodystrophy, Globoid Cell / physiopathology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Motor Neurons / drug effects
  • Motor Neurons / pathology
  • Nerve Fibers / drug effects
  • Nerve Fibers / pathology
  • Psychosine / pharmacology
  • Sciatic Nerve / drug effects
  • Sciatic Nerve / pathology
  • Spinal Cord / drug effects
  • Spinal Cord / pathology


  • Psychosine