Document Detail


Role of cathepsin D in U18666A-induced neuronal cell death: potential implication in Niemann-Pick type C disease pathogenesis.
MedLine Citation:
PMID:  23250759     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Cathepsin D is an aspartyl protease that plays a crucial role in normal cellular functions and in a variety of neurodegenerative disorders, including Niemann-Pick type C (NPC) disease, which is characterized by intracellular accumulation of cholesterol and glycosphingolipids in many tissues, including the brain. There is evidence that the level and activity of cathepsin D increased markedly in vulnerable neurons in NPC pathology, but its involvement in neurodegeneration remains unclear. In the present study, using mouse hippocampal cultured neurons, we evaluated the significance of cathepsin D in toxicity induced by U18666A, a class II amphiphile, which triggers cell death by impairing the trafficking of cholesterol, as observed in NPC pathology. Our results showed that U18666A-mediated toxicity is accompanied by an increase in cathepsin D mRNA and enzyme activity but a decrease in the total peptide content. The cytosolic level of cathepsin D, on the other hand, was increased along with cytochrome c and activated caspase-3 in U18666A-treated neurons. The cathepsin D inhibitor, pepstatin A, partially protected neurons against toxicity by attenuating these signaling mechanisms. Additionally, down-regulation of cathepsin D level prevented, whereas overexpression of the protease increased, vulnerability of cultured N2a cells to U18666A-induced toxicity. We also showed that extracellular cathepsin D from U18666A-treated neurons or application of exogenous enzyme can induce neurotoxicity by activating the autophagic pathway. These results suggest that increased release/activation of cathepsin D can trigger neurodegeneration and possibly development of NPC pathology. Thus, targeting cathepsin D level/activity may provide a new therapeutic opportunity for the treatment of NPC pathology.
Authors:
Asha Amritraj; Yanlin Wang; Timothy J Revett; David Vergote; David Westaway; Satyabrata Kar
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-12-17
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  288     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-02-04     Completed Date:  2013-03-28     Revised Date:  2014-02-04    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3136-52     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Androstenes / toxicity*
Animals
Biological Markers / metabolism
Caspase 3 / metabolism
Cathepsin D / antagonists & inhibitors,  metabolism*
Cell Death / drug effects
Cell Survival / drug effects
Cells, Cultured
Cholesterol / metabolism
Cytochromes c / metabolism
Extracellular Space / drug effects,  metabolism
Fibroblasts / drug effects,  enzymology,  pathology
Hippocampus / pathology
Humans
Mice
Mice, Inbred BALB C
Microtubule-Associated Proteins / metabolism
Neurons / drug effects,  enzymology,  pathology*
Niemann-Pick Disease, Type C / enzymology*,  etiology,  pathology*
Protease Inhibitors / pharmacology
Staurosporine / pharmacology
Grant Support
ID/Acronym/Agency:
MOP-94375//Canadian Institutes of Health Research; MOP-97837//Canadian Institutes of Health Research
Chemical
Reg. No./Substance:
0/Androstenes; 0/Atg5 protein, mouse; 0/Biological Markers; 0/Microtubule-Associated Proteins; 0/Protease Inhibitors; 3039-71-2/3-beta-(2-(diethylamino)ethoxy)androst-5-en-17-one; 9007-43-6/Cytochromes c; 97C5T2UQ7J/Cholesterol; EC 3.4.22.-/Caspase 3; EC 3.4.23.5/Cathepsin D; H88EPA0A3N/Staurosporine
Comments/Corrections

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