Glycogen synthase kinase-3beta inhibitors prevent cellular polyglutamine toxicity caused by the Huntington's disease mutation.
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.
Carmichael
Jenny
J
Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome Trust/Medical Research Council Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY, UK.
Sugars
Katherine L
KL
Bao
Yi Ping
YP
Rubinsztein
David C
DC
D000818:Animals; D019556:COS Cells; D002449:Cell Aggregation / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D003598:Cytoskeletal Proteins / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D055551:HSP27 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis; D006360:Heat-Shock Proteins; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy / Q000235:genetics*; D007211:Indoles / Q000494:pharmacology*; D018021:Lithium Chloride / Q000494:pharmacology*; D008301:Maleimides / Q000494:pharmacology*; D018832:Molecular Chaperones; D009154:Mutation; D009363:Neoplasm Proteins / Q000096:biosynthesis; D010455:Peptides / Q000633:toxicity*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D015534:Trans-Activators / Q000502:physiology; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D055551:HSP27 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D007211:Indoles; D008301:Maleimides; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D010455:Peptides; D019253:Proto-Oncogene Proteins c-bcl-2; C417521:SB 216763; D015534:Trans-Activators; D051176:beta Catenin; C097188:polyglutamine; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride