| Increased activity and altered subcellular distribution of lysosomal enzymes determine neuronal vulnerability in Niemann-Pick type C1-deficient mice. | |
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MedLine Citation:
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PMID: 19893049 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Niemann-Pick disease type C (NPC), caused by mutations in the Npc1 or Npc2 genes, is a progressive neurodegenerative disorder characterized by intracellular accumulation/redistribution of cholesterol in a number of tissues including the brain. This is accompanied by a severe loss of neurons in selected brain regions. In this study, we evaluated the role of lysosomal enzymes, cathepsins B and D, in determining neuronal vulnerability in NPC1-deficient (Npc1(-/-)) mouse brains. Our results showed that Npc1(-/-) mice exhibit an age-dependent degeneration of neurons in the cerebellum but not in the hippocampus. The cellular level/expression and activity of cathepsins B and D are increased more predominantly in the cerebellum than in the hippocampus of Npc1(-/-) mice. In addition, the cytosolic levels of cathepsins, cytochrome c, and Bax2 are higher in the cerebellum than in the hippocampus of Npc1(-/-) mice, suggesting a role for these enzymes in the degeneration of neurons. This suggestion is supported by our observation that degeneration of cultured cortical neurons treated with U18666A, which induces an NPC1-like phenotype at the cellular level, can be attenuated by inhibition of cathepsin B or D enzyme activity. These results suggest that the increased level/activity and altered subcellular distribution of cathepsins may be associated with the underlying cause of neuronal vulnerability in Npc1(-/-) brains. Therefore, their inhibitors may have therapeutic potential in attenuating NPC pathology. |
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Authors:
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Asha Amritraj; Kyle Peake; Anitha Kodam; Chiara Salio; Adalberto Merighi; Jean E Vance; Satyabrata Kar |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2009-11-05 |
Journal Detail:
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Title: The American journal of pathology Volume: 175 ISSN: 1525-2191 ISO Abbreviation: Am. J. Pathol. Publication Date: 2009 Dec |
Date Detail:
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Created Date: 2009-12-07 Completed Date: 2010-02-25 Revised Date: 2011-03-03 |
Medline Journal Info:
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Nlm Unique ID: 0370502 Medline TA: Am J Pathol Country: United States |
Other Details:
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Languages: eng Pagination: 2540-56 Citation Subset: AIM; IM |
Affiliation:
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Department of Psychiatry, Centre for Prions and Protein Folding Diseases, University of Alberta, Alberta, Canada. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cathepsin B / metabolism* Cathepsin D / metabolism* Cerebellum / metabolism, pathology Cholesterol / metabolism Fluorescent Antibody Technique Hippocampus / metabolism, pathology Immunoblotting Lysosomes / enzymology Mice Mice, Inbred BALB C Mice, Knockout Microscopy, Electron, Transmission Nerve Degeneration / enzymology*, pathology Neurons / enzymology, pathology Niemann-Pick Disease, Type C / enzymology*, pathology Proteins / genetics* |
| Grant Support | |
ID/Acronym/Agency:
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//Canadian Institutes of Health Research |
| Chemical | |
Reg. No./Substance:
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0/Npc1 protein, mouse; 0/Proteins; 57-88-5/Cholesterol; EC 3.4.22.1/Cathepsin B; EC 3.4.23.5/Cathepsin D |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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