A toxic monomeric conformer of the polyglutamine protein
A toxic monomeric conformer of the polyglutamine protein
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DOI：
10.1038/nsmb1215
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发表时间：
2007-04-01
影响因子：
16.8
通讯作者：
Toda, Tatsushi
中科院分区：
文献类型：
--
作者：
Nagai, Yoshitaka;Inui, Takashi;Toda, Tatsushi
多聚谷氨酰胺（polyQ）疾病被分类为构象神经退行性疾病，如阿尔茨海默病和帕金森病，并且它们由具有异常扩展的polyQ拉伸的蛋白质引起。然而，构象变化的扩展polyQ蛋白和毒性构象形成的聚集过程中仍然知之甚少，尽管它们在发病机制中的重要作用。在这里，我们表明，β-折叠构象转变的扩展polyQ蛋白单体之前，其组装成β-折叠丰富的淀粉样蛋白样原纤维。将各种polyQ蛋白构象异构体显微注射到培养的细胞中揭示了可溶性β折叠单体引起细胞毒性。polyQ结合肽QBP 1可防止扩展的polyQ蛋白单体的毒性β折叠构象转变。我们的结论是，有毒的构象转变，而不仅仅是聚集过程本身，是polyQ疾病的治疗靶点，并且可能是一般构象疾病的治疗靶点。
Polyglutamine (polyQ) diseases are classified as conformational neurodegenerative diseases, like Alzheimer and Parkinson diseases, and they are caused by proteins with an abnormally expanded polyQ stretch. However, conformational changes of the expanded polyQ protein and the toxic conformers formed during aggregation have remained poorly understood despite their important role in pathogenesis. Here we show that a beta-sheet conformational transition of the expanded polyQ protein monomer precedes its assembly into beta-sheet-rich amyloid-like fibrils. Microinjection of the various polyQ protein conformers into cultured cells revealed that the soluble beta-sheet monomer causes cytotoxicity. The polyQ-binding peptide QBP1 prevents the toxic beta-sheet conformational transition of the expanded polyQ protein monomer. We conclude that the toxic conformational transition, and not simply the aggregation process itself, is a therapeutic target for polyQ diseases and possibly for conformational diseases in general.