Peripheral neuropathy in the Twitcher mouse involves the activation of axonal caspase 3

ASN Neuro. 2011;3(4):e00066. doi: 10.1042/AN20110019.

Abstract

Infantile Krabbe disease results in the accumulation of lipid-raft-associated galactosylsphingosine (psychosine), demyelination, neurodegeneration and premature death. Recently, axonopathy has been depicted as a contributing factor in the progression of neurodegeneration in the Twitcher mouse, a bona fide mouse model of Krabbe disease. Analysis of the temporal-expression profile of MBP (myelin basic protein) isoforms showed unexpected increases of the 14, 17 and 18.5 kDa isoforms in the sciatic nerve of 1-week-old Twitcher mice, suggesting an abnormal regulation of the myelination process during early postnatal life in this mutant. Our studies showed an elevated activation of the pro-apoptotic protease caspase 3 in sciatic nerves of 15- and 30-day-old Twitcher mice, in parallel with increasing demyelination. Interestingly, while active caspase 3 was clearly contained in peripheral axons at all ages, we found no evidence of caspase accumulation in the soma of corresponding mutant spinal cord motor neurons. Furthermore, active caspase 3 was found not only in unmyelinated axons, but also in myelinated axons of the mutant sciatic nerve. These results suggest that axonal caspase activation occurs before demyelination and following a dying-back pattern. Finally, we showed that psychosine was sufficient to activate caspase 3 in motor neuronal cells in vitro in the absence of myelinating glia. Taken together, these findings indicate that degenerating mechanisms actively and specifically mediate axonal dysfunction in Krabbe disease and support the idea that psychosine is a pathogenic sphingolipid sufficient to cause axonal defects independently of demyelination.

Publication types

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

MeSH terms

  • Animals
  • Animals, Newborn
  • Axons / metabolism*
  • Caspase 3 / metabolism*
  • Cell Line, Transformed
  • Ceramides / pharmacology
  • DNA Fragmentation
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Enzyme Activation / drug effects
  • Leukodystrophy, Globoid Cell / complications*
  • Leukodystrophy, Globoid Cell / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Neurologic Mutants
  • Motor Neurons / drug effects
  • Motor Neurons / pathology
  • Myelin Basic Protein / metabolism
  • Neural Conduction / physiology
  • Neurofilament Proteins / metabolism
  • Peripheral Nervous System Diseases / etiology*
  • Peripheral Nervous System Diseases / pathology*
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Psychosine / pharmacology
  • Sciatic Nerve / physiopathology
  • Spinal Cord / metabolism
  • Spinal Cord / pathology

Substances

  • Ceramides
  • Myelin Basic Protein
  • Neurofilament Proteins
  • Protein Isoforms
  • neurofilament protein L
  • N-caproylsphingosine
  • Psychosine
  • Caspase 3