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Neurological deficits and glycosphingolipid accumulation in saposin B deficient mice.

Saposin B derives from the multi-functional precursor, prosaposin, and functions as an activity enhancer for several glycosphingolipid (GSL) hydrolases. Mutations in saposin B present in humans with phenotypes resembling metachromatic leukodystrophy. To gain insight into saposin B's physiological functions, a specific deficiency was created in mice by a knock-in mutation of an essential cysteine in exon 7 of the prosaposin locus. No saposin B protein was detected in the homozygotes (B-/-) mice, whereas prosaposin, and saposins A, C and D were at normal levels. B-/- mice exhibited slowly progressive neuromotor deterioration and minor head tremor by 15 months. Excess hydroxy and non-hydroxy fatty acid sulfatide levels were present in brain and kidney. Alcian blue positive (sulfatide) storage cells were found in the brain, spinal cord and kidney. Ultrastructural analyses showed lamellar inclusion material in the kidney, sciatic nerve, brain and spinal cord tissues. Lactosylceramide (LacCer) and globotriaosylceramide (TriCer) were increased in various tissues of B-/- mice supporting the in vivo role of saposin B in the degradation of these lipids. CD68 positive microglial cells and activated GFAP positive astrocytes showed a proinflammatory response in the brains of B-/- mice. These findings delineate the roles of saposin B for the in vivo degradation of several GSLs and its primary function in maintenance of CNS function. B-/- provide a useful model for understanding the contributions of this saposin to GSL metabolism and homeostasis.

Pubmed ID: 18480170


  • Sun Y
  • Witte DP
  • Ran H
  • Zamzow M
  • Barnes S
  • Cheng H
  • Han X
  • Williams MT
  • Skelton MR
  • Vorhees CV
  • Grabowski GA


Human molecular genetics

Publication Data

August 1, 2008

Associated Grants

  • Agency: NIDDK NIH HHS, Id: P30 DK056341
  • Agency: NIDDK NIH HHS, Id: P30 DK056341-07
  • Agency: NIDDK NIH HHS, Id: P30 DK056341-08
  • Agency: NIA NIH HHS, Id: R01 AG23168
  • Agency: NIEHS NIH HHS, Id: R01 ES 015689
  • Agency: NIDDK NIH HHS, Id: R01 NS/DK36681

Mesh Terms

  • Animals
  • Brain
  • Female
  • Glucosylceramidase
  • Glycosphingolipids
  • Homozygote
  • Kidney
  • Male
  • Mice
  • Mice, Knockout
  • Phenotype
  • Point Mutation
  • Saposins
  • Spinal Cord