Sánchez Ivelisse, Mahlke Christian, Yuan Junying
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Nature. 2003 Jan 23;421(6921):373-9. doi: 10.1038/nature01301.
The expansion of a CAG repeat coding for polyglutamine in otherwise unrelated gene products is central to eight neurodegenerative disorders including Huntington's disease. It has been well documented that expanded polyglutamine fragments, cleaved from their respective full-length proteins, form microscopically visible aggregates in affected individuals and in transgenic mice. The contribution of polyglutamine oligomers to neurodegeneration, however, is controversial. The azo-dye Congo red binds preferentially to beta-sheets containing amyloid fibrils and can specifically inhibit oligomerization and disrupt preformed oligomers. Here we show that inhibition of polyglutamine oligomerization by Congo red prevents ATP depletion and caspase activation, preserves normal cellular protein synthesis and degradation functions, and promotes the clearance of expanded polyglutamine repeats in vivo and in vitro. Infusion of Congo red into a transgenic mouse model of Huntington's disease, well after the onset of symptoms, promotes the clearance of expanded repeats in vivo and exerts marked protective effects on survival, weight loss and motor function. We conclude that oligomerization is a crucial determinant in the biochemical properties of expanded polyglutamine that are central to their chronic cytotoxicity.
在其他不相关的基因产物中，编码聚谷氨酰胺的CAG重复序列的扩增是包括亨廷顿舞蹈症在内的八种神经退行性疾病的核心问题。有充分的文献记载，从各自全长蛋白质上切割下来的扩增聚谷氨酰胺片段，在受影响个体和转基因小鼠中形成显微镜下可见的聚集体。然而，聚谷氨酰胺寡聚物对神经退行性变的作用存在争议。偶氮染料刚果红优先结合含有淀粉样原纤维的β折叠片，并且能特异性抑制寡聚化并破坏预先形成的寡聚物。在此我们表明，刚果红对聚谷氨酰胺寡聚化的抑制作用可防止ATP耗竭和半胱天冬酶激活，维持正常的细胞蛋白质合成和降解功能，并促进体内外扩增聚谷氨酰胺重复序列的清除。在亨廷顿舞蹈症转基因小鼠模型出现症状很久之后，向其注入刚果红，可促进体内扩增重复序列的清除，并对生存、体重减轻和运动功能产生显著的保护作用。我们得出结论，寡聚化是扩增聚谷氨酰胺生化特性的关键决定因素，而这些特性是其慢性细胞毒性的核心。
