Neurological deficits and glycosphingolipid accumulation in saposin B deficient mice

Ying Sun, David P. Witte, Huimin Ran, Matt Zamzow, Sonya Barnes, Hua Cheng, Xianlin Han, Michael T. Williams, Matthew R. Skelton, Charles V. Vorhees, Gregory A. Grabowski

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2345-2356
Number of pages12
JournalHuman Molecular Genetics
Volume17
Issue number15
DOIs
StatePublished - Aug 1 2008
Externally publishedYes

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Saposins
Glycosphingolipids
Sulfoglycosphingolipids
Brain
Kidney
Spinal Cord
mouse saposin B
Metachromatic Leukodystrophy
Alcian Blue
Mutation
Homozygote
Tremor
Hydrolases
Sciatic Nerve
Astrocytes
Cysteine
Exons
Homeostasis

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Sun, Y., Witte, D. P., Ran, H., Zamzow, M., Barnes, S., Cheng, H., ... Grabowski, G. A. (2008). Neurological deficits and glycosphingolipid accumulation in saposin B deficient mice. Human Molecular Genetics, 17(15), 2345-2356. https://doi.org/10.1093/hmg/ddn135

Neurological deficits and glycosphingolipid accumulation in saposin B deficient mice. / Sun, Ying; Witte, David P.; Ran, Huimin; Zamzow, Matt; Barnes, Sonya; Cheng, Hua; Han, Xianlin; Williams, Michael T.; Skelton, Matthew R.; Vorhees, Charles V.; Grabowski, Gregory A.

In: Human Molecular Genetics, Vol. 17, No. 15, 01.08.2008, p. 2345-2356.

Research output: Contribution to journalArticle

Sun, Y, Witte, DP, Ran, H, Zamzow, M, Barnes, S, Cheng, H, Han, X, Williams, MT, Skelton, MR, Vorhees, CV & Grabowski, GA 2008, 'Neurological deficits and glycosphingolipid accumulation in saposin B deficient mice', Human Molecular Genetics, vol. 17, no. 15, pp. 2345-2356. https://doi.org/10.1093/hmg/ddn135
Sun, Ying ; Witte, David P. ; Ran, Huimin ; Zamzow, Matt ; Barnes, Sonya ; Cheng, Hua ; Han, Xianlin ; Williams, Michael T. ; Skelton, Matthew R. ; Vorhees, Charles V. ; Grabowski, Gregory A. / Neurological deficits and glycosphingolipid accumulation in saposin B deficient mice. In: Human Molecular Genetics. 2008 ; Vol. 17, No. 15. pp. 2345-2356.
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AU - Han, Xianlin

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