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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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Ultrastructural studies. (A) The spinal cord of saposin C+/− mice at 18 months had normal morphology. (B) The spinal cord of saposin C−/− mice at 18 months showed inclusion bodies (arrows) in neuronal process. (C) Enlarged view of inclusion bodies in (B). (D) Cortical neuron in saposin C−/− mice at 10 months had normal morphology. (E) Axonal inclusions (arrow) in granule cell layer of saposin C−/− cerebellum at 18 months. (F) Purkinje cells in saposin C−/− mouse at 10 months had normal morphology. (G) The sciatic nerve of saposin C−/− mice at 18 months had inclusion materials (arrows) and degenerating myelin layers (arrowheads). (H) Axonal inclusion material (arrow) in the midbrain of saposin C−/− mice at 18 months.
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DDP531F8: Ultrastructural studies. (A) The spinal cord of saposin C+/− mice at 18 months had normal morphology. (B) The spinal cord of saposin C−/− mice at 18 months showed inclusion bodies (arrows) in neuronal process. (C) Enlarged view of inclusion bodies in (B). (D) Cortical neuron in saposin C−/− mice at 10 months had normal morphology. (E) Axonal inclusions (arrow) in granule cell layer of saposin C−/− cerebellum at 18 months. (F) Purkinje cells in saposin C−/− mouse at 10 months had normal morphology. (G) The sciatic nerve of saposin C−/− mice at 18 months had inclusion materials (arrows) and degenerating myelin layers (arrowheads). (H) Axonal inclusion material (arrow) in the midbrain of saposin C−/− mice at 18 months.

Mentions: Ultrastructural analyses revealed that axonal and neuronal processes contained electron-dense complex membrane whirl inclusions in saposin C−/− mice at 18 months (Fig. 8). The storage inclusion materials are heterogeneous and membrane bound bodies. The inclusion bodies were found in spinal cord, brainstem, midbrain, cortex, hippocampus, cerebellum and sciatic nerve. The sciatic nerve exhibited inclusion bodies and degenerating myelin layers. More neuronal processes containing inclusions were observed at 18 or 22 months than that at 10 months. No inclusions or excesses of multivesicular bodies were found in cerebral neurons or Purkinje cells at 10, 18 and 22 months (Fig. 8).


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)

Ultrastructural studies. (A) The spinal cord of saposin C+/− mice at 18 months had normal morphology. (B) The spinal cord of saposin C−/− mice at 18 months showed inclusion bodies (arrows) in neuronal process. (C) Enlarged view of inclusion bodies in (B). (D) Cortical neuron in saposin C−/− mice at 10 months had normal morphology. (E) Axonal inclusions (arrow) in granule cell layer of saposin C−/− cerebellum at 18 months. (F) Purkinje cells in saposin C−/− mouse at 10 months had normal morphology. (G) The sciatic nerve of saposin C−/− mice at 18 months had inclusion materials (arrows) and degenerating myelin layers (arrowheads). (H) Axonal inclusion material (arrow) in the midbrain of saposin C−/− mice at 18 months.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

DDP531F8: Ultrastructural studies. (A) The spinal cord of saposin C+/− mice at 18 months had normal morphology. (B) The spinal cord of saposin C−/− mice at 18 months showed inclusion bodies (arrows) in neuronal process. (C) Enlarged view of inclusion bodies in (B). (D) Cortical neuron in saposin C−/− mice at 10 months had normal morphology. (E) Axonal inclusions (arrow) in granule cell layer of saposin C−/− cerebellum at 18 months. (F) Purkinje cells in saposin C−/− mouse at 10 months had normal morphology. (G) The sciatic nerve of saposin C−/− mice at 18 months had inclusion materials (arrows) and degenerating myelin layers (arrowheads). (H) Axonal inclusion material (arrow) in the midbrain of saposin C−/− mice at 18 months.
Mentions: Ultrastructural analyses revealed that axonal and neuronal processes contained electron-dense complex membrane whirl inclusions in saposin C−/− mice at 18 months (Fig. 8). The storage inclusion materials are heterogeneous and membrane bound bodies. The inclusion bodies were found in spinal cord, brainstem, midbrain, cortex, hippocampus, cerebellum and sciatic nerve. The sciatic nerve exhibited inclusion bodies and degenerating myelin layers. More neuronal processes containing inclusions were observed at 18 or 22 months than that at 10 months. No inclusions or excesses of multivesicular bodies were found in cerebral neurons or Purkinje cells at 10, 18 and 22 months (Fig. 8).

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