Document Detail


Effects of the cholesterol-lowering compound methyl-beta-cyclodextrin in models of alpha-synucleinopathy.
MedLine Citation:
PMID:  16895578     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The aggregation of alpha-synuclein (alpha-syn) is believed to play a critical role in the pathogenesis of disorders such as dementia with Lewy bodies and Parkinson's disease. The function of alpha-syn remains unclear, although several lines of evidence suggest that alpha-syn is involved in synaptic vesicle trafficking, probably via lipid binding, and interactions with lipids have been shown to regulate alpha-syn aggregation. In this context, the main objective of this study was to determine whether methyl-beta-cyclodextrin (MbetaCD), a cholesterol-extracting agent, interfered with alpha-syn accumulation in models of synucleinopathy. For this purpose, we studied the effects of MbetaCD on the accumulation of alpha-syn in a transfected neuronal cell line and in transgenic mice. Immunoblot analysis showed that MbetaCD reduced the level of alpha-syn in the membrane fraction and detergent-insoluble fraction of transfected cells. In agreement with the in vitro studies, treatment of mice with MbetaCD resulted in decreased levels of alpha-syn in membrane fractions and reduced accumulation of alpha-syn in the neuronal cell body and synapses. Taken together, these results suggest that changes in cholesterol and lipid composition using cholesterol-lowering agents may be used as a tool for the treatment of synucleinopathies.
Authors:
Pazit Bar-On; Edward Rockenstein; Anthony Adame; Gilbert Ho; Makoto Hashimoto; Eliezer Masliah
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Journal of neurochemistry     Volume:  98     ISSN:  0022-3042     ISO Abbreviation:  J. Neurochem.     Publication Date:  2006 Aug 
Date Detail:
Created Date:  2006-08-09     Completed Date:  2006-09-21     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  2985190R     Medline TA:  J Neurochem     Country:  England    
Other Details:
Languages:  eng     Pagination:  1032-45     Citation Subset:  IM    
Affiliation:
Department of Neurosciences, University of California, San Diego, La Jolla, 92093-0624, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Anticholesteremic Agents / pharmacology*
Blotting, Western
Brain Chemistry
Cell Line
Cell Membrane / metabolism
Cell Survival / drug effects
Centrifugation, Density Gradient
Cholesterol / metabolism
Humans
Immunoblotting
Immunohistochemistry
Mice
Mice, Transgenic
Neurons / metabolism
Neuroprotective Agents*
Neurotoxicity Syndromes / metabolism,  prevention & control*
Nuclease Protection Assays
alpha-Synuclein / metabolism,  physiology*
beta-Cyclodextrins / pharmacology*
Grant Support
ID/Acronym/Agency:
AG022074/AG/NIA NIH HHS; AG05131/AG/NIA NIH HHS; AG18440/AG/NIA NIH HHS
Chemical
Reg. No./Substance:
0/Anticholesteremic Agents; 0/Neuroprotective Agents; 0/alpha-Synuclein; 0/beta-Cyclodextrins; 0/methyl-beta-cyclodextrin; 57-88-5/Cholesterol

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


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