| Altered cholesterol homeostasis contributes to enhanced excitotoxicity in Huntington's disease. | |
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MedLine Citation:
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PMID: 20663016 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Recent findings suggest that altered cholesterol homeostasis may contribute to the pathophysiology of Huntington's disease (HD). To understand the underlying mechanisms, here we used a combination of two-photon microscopy, epifluorescence, and biochemical methods to visualize and quantify lipid distribution in cell cultures expressing mutant huntingtin. Such expression promotes lipid imbalance, and cholesterol accumulation in cellular and murine models and in HD-affected human brains. Interestingly, cells expressing mutant huntingtin also showed higher content of ordered domains in their plasma membranes. These findings correlated with high levels of caveolin-1 and glycosphingolipid GM1, two well-defined markers of cholesterol-enriched domains, at the cell surface. In addition, cells expressing mutant huntingtin showed increased localization of NMDA receptors with cholesterol-enriched domains, contributing to increased NMDA receptor susceptibility to excitotoxic insults. Treatment with simvastatin or β-cyclodextrin, two cholesterol-lowering drugs, reduced the content of ordered domains at the cell surface, which in turn, protected cells against NMDA-mediated excitotoxicity. Taken together, our results indicate that mutant huntingtin produces accumulation of cholesterol and alters its cellular distribution that contributes to NMDA-mediated excitotoxicity. Administration of drugs that recover this effect, such as simvastatin could be beneficial for the treatment of HD. |
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Authors:
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Daniel del Toro; Xavier Xifró; Albert Pol; Sandrine Humbert; Frédéric Saudou; Josep M Canals; Jordi Alberch |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-08-12 |
Journal Detail:
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Title: Journal of neurochemistry Volume: 115 ISSN: 1471-4159 ISO Abbreviation: J. Neurochem. Publication Date: 2010 Oct |
Date Detail:
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Created Date: 2010-09-15 Completed Date: 2010-10-13 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 2985190R Medline TA: J Neurochem Country: England |
Other Details:
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Languages: eng Pagination: 153-67 Citation Subset: IM |
Copyright Information:
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© 2010 The Authors. Journal Compilation © 2010 International Society for Neurochemistry. |
Affiliation:
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Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Anticholesteremic Agents / pharmacology Brain / pathology Caveolin 1 / metabolism Cell Membrane / metabolism Cell Survival Cells, Cultured Cholesterol / metabolism* DNA / genetics Excitatory Amino Acid Agonists / pharmacology* Fluorescent Antibody Technique Homeostasis / physiology Humans Huntington Disease / metabolism*, pathology* Indicators and Reagents Membrane Microdomains / metabolism Mice Mice, Transgenic N-Methylaspartate / pharmacology* Neostriatum / cytology, metabolism Nerve Tissue Proteins / genetics Nuclear Proteins / genetics Simvastatin / pharmacology Transfection Triglycerides / metabolism beta-Cyclodextrins / pharmacology |
| Chemical | |
Reg. No./Substance:
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0/Anticholesteremic Agents; 0/Caveolin 1; 0/Excitatory Amino Acid Agonists; 0/Huntington protein, mouse; 0/Indicators and Reagents; 0/Nerve Tissue Proteins; 0/Nuclear Proteins; 0/Triglycerides; 0/beta-Cyclodextrins; 57-88-5/Cholesterol; 6384-92-5/N-Methylaspartate; 79902-63-9/Simvastatin; 9007-49-2/DNA |
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