1. Iminosugar-based inhibitors of glucosylceramide synthase prolong survival but paradoxically increase brain glucosylceramide levels in Niemann-Pick C mice.
- Author
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Nietupski JB, Pacheco JJ, Chuang WL, Maratea K, Li L, Foley J, Ashe KM, Cooper CG, Aerts JM, Copeland DP, Scheule RK, Cheng SH, and Marshall J
- Subjects
- Animals, Brain cytology, Brain drug effects, Disease Models, Animal, Drug Synergism, Glucosylceramides metabolism, Glycosphingolipids metabolism, Liver cytology, Liver drug effects, Liver metabolism, Mice, Mice, Inbred BALB C, Mice, Knockout, Niemann-Pick Disease, Type C enzymology, Survival Rate, Brain metabolism, Enzyme Inhibitors therapeutic use, Glucosyltransferases antagonists & inhibitors, Imino Sugars therapeutic use, Niemann-Pick Disease, Type C drug therapy, Niemann-Pick Disease, Type C mortality
- Abstract
Niemann Pick type C (NPC) disease is a progressive neurodegenerative disease caused by mutations in NPC1 or NPC2, the gene products of which are involved in cholesterol transport in late endosomes. NPC is characterized by an accumulation of cholesterol, sphingomyelin and glycosphingolipids in the visceral organs, primarily the liver and spleen. In the brain, there is a redistribution of unesterified cholesterol and a concomitant accumulation of glycosphingolipids. It has been suggested that reducing the aberrant lysosomal storage of glycosphingolipids in the brain by a substrate reduction therapy (SRT) approach may prove beneficial. Inhibiting glucosylceramide synthase (GCS) using the iminosugar-based inhibitor miglustat (NB-DNJ) has been reported to increase the survival of NPC mice. Here, we tested the effects of Genz-529468, a more potent iminosugar-based inhibitor of GCS, in the NPC mouse. Oral administration of Genz-529468 or NB-DNJ to NPC mice improved their motor function, reduced CNS inflammation, and increased their longevity. However, Genz-529468 offered a wider therapeutic window and better therapeutic index than NB-DNJ. Analysis of the glycolipids in the CNS of the iminosugar-treated NPC mouse revealed that the glucosylceramide (GL1) but not the ganglioside levels were highly elevated. This increase in GL1 was likely caused by the off-target inhibition of the murine non-lysosomal glucosylceramidase, Gba2. Hence, the basis for the observed effects of these inhibitors in NPC mice might be related to their inhibition of Gba2 or another unintended target rather than a result of substrate reduction., (Copyright © 2012 Elsevier Inc. All rights reserved.)
- Published
- 2012
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