Abstract | BACKGROUND: METHODOLOGY/PRINCIPAL FINDINGS: Administration of CD to Npc1(-/-) mice beginning at either P7 or P21 and continuing every other day delayed clinical onset, reduced intraneuronal cholesterol and GSL storage as well as free sphingosine accumulation, reduced markers of neurodegeneration, and led to longer survival than any previous treatment regime. We reasoned that other lysosomal diseases characterized by cholesterol and GSL accumulation, including NPC disease due to NPC2 deficiency, GM1 gangliosidosis and mucopolysaccharidosis (MPS) type IIIA, might likewise benefit from CD treatment. Treated Npc2(-/-) mice showed benefits similar to NPC1 disease, however, mice with GM1 gangliosidosis or MPS IIIA failed to show reduction in storage. CONCLUSIONS/SIGNIFICANCE: Treatment with CD delayed clinical disease onset, reduced intraneuronal storage and secondary markers of neurodegeneration, and significantly increased lifespan of both Npc1(-/-) and Npc2(-/-) mice. In contrast, CD failed to ameliorate cholesterol or glycosphingolipid storage in GM1 gangliosidosis and MPS IIIA disease. Understanding the mechanism(s) by which CD leads to reduced neuronal storage may provide important new opportunities for treatment of NPC and related neurodegenerative diseases characterized by cholesterol dyshomeostasis.
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Authors | Cristin D Davidson, Nafeeza F Ali, Matthew C Micsenyi, Gloria Stephney, Sophie Renault, Kostantin Dobrenis, Daniel S Ory, Marie T Vanier, Steven U Walkley |
Journal | PloS one
(PLoS One)
Vol. 4
Issue 9
Pg. e6951
(Sep 11 2009)
ISSN: 1932-6203 [Electronic] United States |
PMID | 19750228
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Cyclodextrins
- Enzyme Inhibitors
- Glycosphingolipids
- beta-Cyclodextrins
- 1-Deoxynojirimycin
- 2-Hydroxypropyl-beta-cyclodextrin
- Cholesterol
- miglustat
- Pregnanolone
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Topics |
- 1-Deoxynojirimycin
(administration & dosage, analogs & derivatives)
- 2-Hydroxypropyl-beta-cyclodextrin
- Animals
- Cholesterol
(metabolism)
- Cyclodextrins
(administration & dosage)
- Disease Models, Animal
- Disease Progression
- Drug Synergism
- Enzyme Inhibitors
(therapeutic use)
- Glycosphingolipids
(metabolism)
- Mice
- Mice, Transgenic
- Neurons
(metabolism)
- Niemann-Pick Disease, Type C
(drug therapy)
- Pregnanolone
(administration & dosage)
- Treatment Outcome
- beta-Cyclodextrins
(administration & dosage)
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