Cargando…
Specific saposin C deficiency: CNS impairment and acid β-glucosidase effects in the mouse
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 β-glucosidase (GCase). The in vivo...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2010
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2807372/ https://www.ncbi.nlm.nih.gov/pubmed/20015957 http://dx.doi.org/10.1093/hmg/ddp531 |
_version_ | 1782176397253410816 |
---|---|
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. |
author_facet | 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. |
author_sort | Sun, Ying |
collection | PubMed |
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 β-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. |
format | Text |
id | pubmed-2807372 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-28073722010-01-19 Specific saposin C deficiency: CNS impairment and acid β-glucosidase effects in the mouse 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. Hum Mol Genet Articles 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 β-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. Oxford University Press 2010-02-15 2009-12-16 /pmc/articles/PMC2807372/ /pubmed/20015957 http://dx.doi.org/10.1093/hmg/ddp531 Text en © The Author 2009. Published by Oxford University Press http://creativecommons.org/licenses/by-nc/2.0/uk/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Articles 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. Specific saposin C deficiency: CNS impairment and acid β-glucosidase effects in the mouse |
title | Specific saposin C deficiency: CNS impairment and acid β-glucosidase effects in the mouse |
title_full | Specific saposin C deficiency: CNS impairment and acid β-glucosidase effects in the mouse |
title_fullStr | Specific saposin C deficiency: CNS impairment and acid β-glucosidase effects in the mouse |
title_full_unstemmed | Specific saposin C deficiency: CNS impairment and acid β-glucosidase effects in the mouse |
title_short | Specific saposin C deficiency: CNS impairment and acid β-glucosidase effects in the mouse |
title_sort | specific saposin c deficiency: cns impairment and acid β-glucosidase effects in the mouse |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2807372/ https://www.ncbi.nlm.nih.gov/pubmed/20015957 http://dx.doi.org/10.1093/hmg/ddp531 |
work_keys_str_mv | AT sunying specificsaposincdeficiencycnsimpairmentandacidbglucosidaseeffectsinthemouse AT ranhuimin specificsaposincdeficiencycnsimpairmentandacidbglucosidaseeffectsinthemouse AT zamzowmatt specificsaposincdeficiencycnsimpairmentandacidbglucosidaseeffectsinthemouse AT kitatanikazuyuki specificsaposincdeficiencycnsimpairmentandacidbglucosidaseeffectsinthemouse AT skeltonmatthewr specificsaposincdeficiencycnsimpairmentandacidbglucosidaseeffectsinthemouse AT williamsmichaelt specificsaposincdeficiencycnsimpairmentandacidbglucosidaseeffectsinthemouse AT vorheescharlesv specificsaposincdeficiencycnsimpairmentandacidbglucosidaseeffectsinthemouse AT wittedavidp specificsaposincdeficiencycnsimpairmentandacidbglucosidaseeffectsinthemouse AT hannunyusufa specificsaposincdeficiencycnsimpairmentandacidbglucosidaseeffectsinthemouse AT grabowskigregorya specificsaposincdeficiencycnsimpairmentandacidbglucosidaseeffectsinthemouse |