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    
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.
Asha Amritraj; Yanlin Wang; Timothy J Revett; David Vergote; David Westaway; Satyabrata Kar
Related Documents :
23900139 - Programmed cell death is impaired in the developing brain of fmr1 mutants.
23752939 - Superimposed topographic and chemical cues synergistically guide neurite outgrowth.
8341139 - Catastrophic visual loss due to cryptococcus neoformans meningitis.
23785139 - Tripartite organization of the ventral stream by animacy and object size.
24177349 - Ondansetron reduces lasting vestibular deficits in a model of severe peripheral excitot...
23537659 - Thymoquinone protects cultured rat primary neurons against amyloid β-induced neurotoxic...
7703419 - A morphometric classification of pupal honeybee antennal lobe neurones in culture.
8890279 - Synaptic interactions between a muscle-associated proprioceptor and body wall muscle mo...
15665939 - Free radical lipid oxidation in brain cortex neurons and neuroglia during convulsions.
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    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Androstenes / toxicity*
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
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
MOP-94375//Canadian Institutes of Health Research; MOP-97837//Canadian Institutes of Health Research
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 D; H88EPA0A3N/Staurosporine

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Previous Document:  Assembly and function of the regulator of G protein signaling 14 (RGS14)·H-Ras signaling complex in ...
Next Document:  Redundancy gain for semantic features.