Glycogen synthase kinase-3β inhibitors prevent cellular polyglutamine toxicity caused by the Huntington's disease mutation
Glycogen synthase kinase-3β inhibitors prevent cellular polyglutamine toxicity caused by the Huntington's disease mutation
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DOI：
10.1074/jbc.m204861200
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发表时间：
2002-09-13
影响因子：
4.8
通讯作者：
Rubinsztein, DC
中科院分区：
文献类型：
--
作者：
Carmichael, J;Sugars, KL;Rubinsztein, DC
亨廷顿氏病是九种已知的神经退行性疾病之一，由疾病蛋白中的多聚谷氨酰胺（poly（Q））链扩展引起。这些疾病与神经元内蛋白质聚集体有关。热诱导型分子伴侣如HSP 70和HSP 27抑制聚（Q）聚集和/或毒性/细胞死亡。包括HSF-1在内的热休克转录因子调节HSP 70和HSP 27的表达。HSF-1活性被糖原合成酶激酶-3（GSK-3）降低，并被GSK-3抑制剂（如锂）增强。因此，我们假设锂治疗可以部分挽救亨廷顿病细胞模型中的死亡。LiCl降低了神经元和非神经元细胞系中聚（Q）的毒性，但这与HSP 70或HSP 27的升高无关。锂的保护作用涉及GSK-3 β抑制，因为GSK-3 β抑制剂SB 216763和显性阴性GSK-3 β突变体的过表达也降低了聚（Q）毒性。LiCl和SB 216763增加β-连环蛋白依赖性T细胞因子介导的转录。由于β-连环蛋白过表达保护细胞免受poly（Q）毒性，我们测试了该途径是否受到poly（Q）扩增突变的损害。与表达野生型构建体的细胞相比，表达扩增重复序列的细胞具有与T细胞因子介导的转录平行降低相关的降低的β-连环蛋白水平。由于氯化锂可以防止多聚谷氨酰胺毒性的细胞系，它是一个很好的候选人，进一步在体内治疗试验。
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.