Iminosugar-based inhibitors of glucosylceramide synthase increase brain glycosphingolipids and survival in a mouse model of Sandhoff disease.

The neuropathic glycosphingolipidoses are a subgroup of lysosomal storage disorders for which there are no effective therapies. A potential approach is substrate reduction therapy using inhibitors of glucosylceramide synthase (GCS) to decrease the synthesis of glucosylceramide and related glycosphin...

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Autores principales:	Karen M Ashe, Dinesh Bangari, Lingyun Li, Mario A Cabrera-Salazar, Scott D Bercury, Jennifer B Nietupski, Christopher G F Cooper, Johannes M F G Aerts, Edward R Lee, Diane P Copeland, Seng H Cheng, Ronald K Scheule, John Marshall
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/cd3e8f6aa28047d9b5d2eaa2ee1c6e5d
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spelling	oai:doaj.org-article:cd3e8f6aa28047d9b5d2eaa2ee1c6e5d2021-11-18T06:50:58ZIminosugar-based inhibitors of glucosylceramide synthase increase brain glycosphingolipids and survival in a mouse model of Sandhoff disease.1932-620310.1371/journal.pone.0021758https://doaj.org/article/cd3e8f6aa28047d9b5d2eaa2ee1c6e5d2011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21738789/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203The neuropathic glycosphingolipidoses are a subgroup of lysosomal storage disorders for which there are no effective therapies. A potential approach is substrate reduction therapy using inhibitors of glucosylceramide synthase (GCS) to decrease the synthesis of glucosylceramide and related glycosphingolipids that accumulate in the lysosomes. Genz-529468, a blood-brain barrier-permeant iminosugar-based GCS inhibitor, was used to evaluate this concept in a mouse model of Sandhoff disease, which accumulates the glycosphingolipid GM2 in the visceral organs and CNS. As expected, oral administration of the drug inhibited hepatic GM2 accumulation. Paradoxically, in the brain, treatment resulted in a slight increase in GM2 levels and a 20-fold increase in glucosylceramide levels. The increase in brain glucosylceramide levels might be due to concurrent inhibition of the non-lysosomal glucosylceramidase, Gba2. Similar results were observed with NB-DNJ, another iminosugar-based GCS inhibitor. Despite these unanticipated increases in glycosphingolipids in the CNS, treatment nevertheless delayed the loss of motor function and coordination and extended the lifespan of the Sandhoff mice. These results suggest that the CNS benefits observed in the Sandhoff mice might not necessarily be due to substrate reduction therapy but rather to off-target effects.Karen M AsheDinesh BangariLingyun LiMario A Cabrera-SalazarScott D BercuryJennifer B NietupskiChristopher G F CooperJohannes M F G AertsEdward R LeeDiane P CopelandSeng H ChengRonald K ScheuleJohn MarshallPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 6, p e21758 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Karen M Ashe Dinesh Bangari Lingyun Li Mario A Cabrera-Salazar Scott D Bercury Jennifer B Nietupski Christopher G F Cooper Johannes M F G Aerts Edward R Lee Diane P Copeland Seng H Cheng Ronald K Scheule John Marshall Iminosugar-based inhibitors of glucosylceramide synthase increase brain glycosphingolipids and survival in a mouse model of Sandhoff disease.
description	The neuropathic glycosphingolipidoses are a subgroup of lysosomal storage disorders for which there are no effective therapies. A potential approach is substrate reduction therapy using inhibitors of glucosylceramide synthase (GCS) to decrease the synthesis of glucosylceramide and related glycosphingolipids that accumulate in the lysosomes. Genz-529468, a blood-brain barrier-permeant iminosugar-based GCS inhibitor, was used to evaluate this concept in a mouse model of Sandhoff disease, which accumulates the glycosphingolipid GM2 in the visceral organs and CNS. As expected, oral administration of the drug inhibited hepatic GM2 accumulation. Paradoxically, in the brain, treatment resulted in a slight increase in GM2 levels and a 20-fold increase in glucosylceramide levels. The increase in brain glucosylceramide levels might be due to concurrent inhibition of the non-lysosomal glucosylceramidase, Gba2. Similar results were observed with NB-DNJ, another iminosugar-based GCS inhibitor. Despite these unanticipated increases in glycosphingolipids in the CNS, treatment nevertheless delayed the loss of motor function and coordination and extended the lifespan of the Sandhoff mice. These results suggest that the CNS benefits observed in the Sandhoff mice might not necessarily be due to substrate reduction therapy but rather to off-target effects.
format	article
author	Karen M Ashe Dinesh Bangari Lingyun Li Mario A Cabrera-Salazar Scott D Bercury Jennifer B Nietupski Christopher G F Cooper Johannes M F G Aerts Edward R Lee Diane P Copeland Seng H Cheng Ronald K Scheule John Marshall
author_facet	Karen M Ashe Dinesh Bangari Lingyun Li Mario A Cabrera-Salazar Scott D Bercury Jennifer B Nietupski Christopher G F Cooper Johannes M F G Aerts Edward R Lee Diane P Copeland Seng H Cheng Ronald K Scheule John Marshall
author_sort	Karen M Ashe
title	Iminosugar-based inhibitors of glucosylceramide synthase increase brain glycosphingolipids and survival in a mouse model of Sandhoff disease.
title_short	Iminosugar-based inhibitors of glucosylceramide synthase increase brain glycosphingolipids and survival in a mouse model of Sandhoff disease.
title_full	Iminosugar-based inhibitors of glucosylceramide synthase increase brain glycosphingolipids and survival in a mouse model of Sandhoff disease.
title_fullStr	Iminosugar-based inhibitors of glucosylceramide synthase increase brain glycosphingolipids and survival in a mouse model of Sandhoff disease.
title_full_unstemmed	Iminosugar-based inhibitors of glucosylceramide synthase increase brain glycosphingolipids and survival in a mouse model of Sandhoff disease.
title_sort	iminosugar-based inhibitors of glucosylceramide synthase increase brain glycosphingolipids and survival in a mouse model of sandhoff disease.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/cd3e8f6aa28047d9b5d2eaa2ee1c6e5d
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Iminosugar-based inhibitors of glucosylceramide synthase increase brain glycosphingolipids and survival in a mouse model of Sandhoff disease.

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