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

Sun Y, Ran H, Zamzow M, Kitatani K, Skelton MR, Williams MT, Vorhees CV, Witte DP, Hannun YA, Grabowski GA - Hum. Mol. Genet. (2009)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

ABSTRACT
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.

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Related in: MedlinePlus

Phenotype of saposin C−/− mice at 16 months. (Left) Saposin C−/− mouse showing hind paw spreading suggesting paralysis. (Right) Saposin C−/− mouse with abnormal hindleg positioning and WT mouse with a normal V shape position in tail-hanging reflex.
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DDP531F3: Phenotype of saposin C−/− mice at 16 months. (Left) Saposin C−/− mouse showing hind paw spreading suggesting paralysis. (Right) Saposin C−/− mouse with abnormal hindleg positioning and WT mouse with a normal V shape position in tail-hanging reflex.

Mentions: Saposin C−/− mice slowly developed neurological impairment and lived up to 24 months. The onset of neurological deficits began at 10–12 months with progressive wobbling, lack of coordination, hind limb weakness and abnormal leg reflexes (Fig. 3). Ataxia developed after 12 months. No differences in phenotype were observed between males and females.


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

Sun Y, Ran H, Zamzow M, Kitatani K, Skelton MR, Williams MT, Vorhees CV, Witte DP, Hannun YA, Grabowski GA - Hum. Mol. Genet. (2009)

Phenotype of saposin C−/− mice at 16 months. (Left) Saposin C−/− mouse showing hind paw spreading suggesting paralysis. (Right) Saposin C−/− mouse with abnormal hindleg positioning and WT mouse with a normal V shape position in tail-hanging reflex.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2807372&req=5

DDP531F3: Phenotype of saposin C−/− mice at 16 months. (Left) Saposin C−/− mouse showing hind paw spreading suggesting paralysis. (Right) Saposin C−/− mouse with abnormal hindleg positioning and WT mouse with a normal V shape position in tail-hanging reflex.
Mentions: Saposin C−/− mice slowly developed neurological impairment and lived up to 24 months. The onset of neurological deficits began at 10–12 months with progressive wobbling, lack of coordination, hind limb weakness and abnormal leg reflexes (Fig. 3). Ataxia developed after 12 months. No differences in phenotype were observed between males and females.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus