Human Molecular Genetics Advance Access originally published online on May 14, 2008
Human Molecular Genetics 2008 17(15):2345-2356; doi:10.1093/hmg/ddn135
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Neurological deficits and glycosphingolipid accumulation in saposin B deficient mice
1 Division of Human Genetics 2 Division of Neurology 3 Division of Pediatric Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA 4 Department of Pediatrics 5 Department of Pathology, University of Cincinnati College of Medicine, Cincinnati, OH 45229-3039, USA 6 Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, USA
* To whom correspondence should be addressed at: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 4006, Cincinnati, OH 45229-3039, USA. Tel: +1 5136367290; Fax: +1 5136362261; Email: greg.grabowski{at}cchmc.org
Received March 13, 2008; Accepted April 21, 2008
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.