Document Detail


Glycogen synthase kinase-3beta inhibitors prevent cellular polyglutamine toxicity caused by the Huntington's disease mutation.
MedLine Citation:
PMID:  12097329     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Huntington's disease is one of nine known neurodegenerative disorders caused by an expanded polyglutamine (poly(Q)) tract in the disease protein. These diseases are associated with intraneuronal protein aggregates. Heat-inducible chaperones like HSP70 and HSP27 suppress poly(Q) aggregation and/or toxicity/cell death. Heat shock transcription factors, including HSF-1, regulate HSP70 and HSP27 expression. HSF-1 activity is reduced by glycogen synthase kinase-3 (GSK-3) and enhanced by GSK-3 inhibitors, like lithium. Thus, we hypothesized that lithium treatment may partially rescue death in Huntington's disease cell models. LiCl reduced poly(Q) toxicity in neuronal and nonneuronal cell lines, but this was not associated with elevation of HSP70 or HSP27. The protective effect of lithium involved GSK-3beta inhibition, since poly(Q) toxicity was also reduced by SB216763, a GSK-3beta inhibitor, and by overexpression of a dominant-negative GSK-3beta mutant. LiCl and SB216763 increased beta-catenin-dependent T-cell factor-mediated transcription. Since beta-catenin overexpression protected cells from poly(Q) toxicity, we tested whether this pathway was impaired by a poly(Q) expansion mutation. Cells expressing expanded repeats had reduced beta-catenin levels associated with a parallel decrease in T-cell factor-mediated transcription, compared with cells expressing wild type constructs. Since LiCl can protect against polyglutamine toxicity in cell lines, it is an excellent candidate for further in vivo therapeutic trials.
Authors:
Jenny Carmichael; Katherine L Sugars; Yi Ping Bao; David C Rubinsztein
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2002-07-03
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  277     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2002 Sep 
Date Detail:
Created Date:  2002-09-09     Completed Date:  2002-12-03     Revised Date:  2011-11-02    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  33791-8     Citation Subset:  IM    
Affiliation:
Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome Trust/Medical Research Council Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY, UK.
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MeSH Terms
Descriptor/Qualifier:
Animals
COS Cells
Cell Aggregation / drug effects
Cell Death / drug effects
Cytoskeletal Proteins / physiology
Enzyme Inhibitors / pharmacology*,  therapeutic use
Glycogen Synthase Kinase 3 / antagonists & inhibitors*
HSP27 Heat-Shock Proteins
HSP70 Heat-Shock Proteins / biosynthesis
Heat-Shock Proteins*
Humans
Huntington Disease / drug therapy,  genetics*
Indoles / pharmacology*
Lithium Chloride / pharmacology*
Maleimides / pharmacology*
Mutation*
Neoplasm Proteins / biosynthesis
Peptides / toxicity*
Proto-Oncogene Proteins c-bcl-2 / biosynthesis
Trans-Activators / physiology
Transcription, Genetic
Tumor Cells, Cultured
beta Catenin
Chemical
Reg. No./Substance:
0/CTNNB1 protein, human; 0/Cytoskeletal Proteins; 0/Enzyme Inhibitors; 0/HSP27 Heat-Shock Proteins; 0/HSP70 Heat-Shock Proteins; 0/HSPB1 protein, human; 0/Heat-Shock Proteins; 0/Indoles; 0/Maleimides; 0/Neoplasm Proteins; 0/Peptides; 0/Proto-Oncogene Proteins c-bcl-2; 0/SB 216763; 0/Trans-Activators; 0/beta Catenin; 26700-71-0/polyglutamine; 7447-41-8/Lithium Chloride; EC 2.7.11.1/glycogen synthase kinase 3 beta; EC 2.7.11.26/Glycogen Synthase Kinase 3

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


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