Comparative clinico-pathological study of saposin-A-deficient (SAP-A-/-) and Twitcher mice

J Neuropathol Exp Neurol. 2004 Jul;63(7):721-34. doi: 10.1093/jnen/63.7.721.

Abstract

The Twitcher mouse (twi/twi) has been widely used as an animal model of globoid cell leukodystrophy (GLD; Krabbe disease), a hereditary leukodystrophy due to genetic galactosylceramidase deficiency. Recently, we generated a new mouse model of late-onset, chronic GLD (SAP-A-/- mice) by introducing a mutation (C106F) in the saposin A domain of the sphingolipid activator protein gene. Comparative study of SAP-A-/- and twi/twi mice revealed delay in the onset of neurological symptoms in SAP-A-/- mice (90 days vs 20 to 25 days), milder symptoms, and prolonged average survival (134.4 +/- 29.1 days vs 47.5 +/- 3.9 days). However, in both, the earliest sites of demyelination and macrophage infiltration were in regions of the 8th nerve and the spinal tract of the 5th nerve and spinal-cord, where macrophages could be detected as early as day 30 in asymptomatic SAP-A-/- mice. Furthermore, spacio-temporal pattern of demyelination/macrophage infiltration and the extent of neuropathology at the terminal stage are closely similar in both. These results suggest that peripheral macrophages are readily accessible in these sites and participate in the demyelinating process in the central nervous system.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Age of Onset
  • Animals
  • Astrocytes / metabolism
  • Astrocytes / pathology
  • Blood-Brain Barrier / physiology
  • Central Nervous System / metabolism
  • Central Nervous System / pathology*
  • Central Nervous System / physiopathology
  • Chemotaxis, Leukocyte / genetics
  • Demyelinating Diseases / genetics
  • Demyelinating Diseases / pathology
  • Demyelinating Diseases / physiopathology
  • Disease Models, Animal
  • Female
  • Galactosylceramidase / deficiency*
  • Glycoproteins / deficiency*
  • Glycoproteins / genetics
  • Glycoproteins / metabolism
  • Leukodystrophy, Globoid Cell / genetics
  • Leukodystrophy, Globoid Cell / pathology*
  • Leukodystrophy, Globoid Cell / physiopathology
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Neurologic Mutants
  • Nerve Degeneration / metabolism
  • Nerve Degeneration / pathology*
  • Oligodendroglia / metabolism
  • Oligodendroglia / pathology
  • Protein Structure, Tertiary / genetics
  • Saposins
  • Sphingolipid Activator Proteins
  • Survival Rate

Substances

  • Glycoproteins
  • Saposins
  • Sphingolipid Activator Proteins
  • Galactosylceramidase