Specific saposin C deficiency: CNS impairment and acid β-glucosidase effects in the mouse

Details

• Alternative Title:
  Hum Mol Genet
• Personal Author:
  Sun, Ying ; Ran, Huimin ; Zamzow, Matt ; Kitatani, Kazuyuki ; Skelton, Matthew R. ; Williams, Michael T. ; Vorhees, Charles V. ; Witte, David P. ; Hannun, Yusuf A. ; Grabowski, Gregory A.
• Description:
  Saposins A, B, C and D are derived from a common precursor, prosaposin (psap). The few patients with saposin C deficiency develop a Gaucher disease-like central nervous system (CNS) phenotype attributed to diminished glucosylceramide (GC) cleavage activity by acid beta-glucosidase (GCase). The in vivo effects of saposin C were examined by creating mice with selective absence of saposin C (C-/-) using a knock-in point mutation (cysteine-to-proline) in exon 11 of the psap gene. In C-/- mice, prosaposin and saposins A, B and D proteins were present at near wild-type levels, but the saposin C protein was absent. By 1 year, the C-/- mice exhibited weakness of the hind limbs and progressive ataxia. Decreased neuromotor activity and impaired hippocampal long-term potentiation were evident. Foamy storage cells were observed in dorsal root ganglion and there was progressive loss of cerebellar Purkinje cells and atrophy of cerebellar granule cells. Ultrastructural analyses revealed inclusions in axonal processes in the spinal cord, sciatic nerve and brain, but no excess of multivesicular bodies. Activated microglial cells and astrocytes were present in thalamus, brain stem, cerebellum and spinal cord, indicating regional pro-inflammatory responses. No storage cells were found in visceral organs of these mice. The absence of saposin C led to moderate increases in GC and lactosylceramide (LacCer) and their deacylated analogues. These results support the view that saposin C has multiple roles in glycosphingolipid (GSL) catabolism as well as a prominent function in CNS and axonal integrity independent of its role as an optimizer/stabilizer of GCase.
• Subjects:
  Animals Behavior, Animal Central Nervous System Disease Models, Animal Female Gaucher Disease Glucosylceramidase Glycosphingolipids Humans Male Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Purkinje Cells Saposins

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• Source:
  Hum Mol Genet. 19(4):634-647.
• Pubmed ID:
  20015957
• Pubmed Central ID:
  PMC2807372
• Document Type:
  Journal Article
• Funding:
  C06PR018823/PR/OCPHP CDC HHS/United States ; R01 DK036729/DK/NIDDK NIH HHS/United States ; R01 NS/DK 36681/DK/NIDDK NIH HHS/United States ; R01ES 015689/ES/NIEHS NIH HHS/United States
• Volume:
  19
• Issue:
  4
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:9b199f9cdc378f60983eb2f7502404d520001cf0f889f46531b0bcbe32a8ef9e
• Download URL:
  https://stacks.cdc.gov/view/cdc/22926/cdc_22926_DS1.pdf
• File Type:
  [PDF - 827.29 KB ]