Self-assembly of polyglutamine-containing huntingtin fragments into amyloid-like fibrils: Implications for Huntington's disease pathology
Self-assembly of polyglutamine-containing huntingtin fragments into amyloid-like fibrils: Implications for Huntington's disease pathology
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DOI：
10.1073/pnas.96.8.4604
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发表时间：
1999-04-13
影响因子：
11.1
通讯作者：
Wanker, EE
中科院分区：
文献类型：
--
作者：
Scherzinger, E;Sittler, A;Wanker, EE
亨廷顿氏病是一种进行性神经退行性疾病，由亨廷顿蛋白第一外显子的聚谷氨酰胺（poly(Q)）重复扩增引起。先前，我们发现在病理范围（51-122谷氨酰胺）具有聚(Q)束的n端亨廷顿肽，而在正常范围（20和30谷氨酰胺）具有聚(Q)束的n端亨廷顿肽，形成具有纤维状或带状形态的高分子量蛋白质聚集体，使人联想到痒病朊蛋白棒和阿尔茨海默病的β -淀粉样原纤维。在这里，我们报道淀粉样亨廷顿蛋白聚集体在体外的形成不仅取决于多(Q)重复长度，而且关键取决于蛋白质浓度和时间。此外，亨廷顿蛋白的体外聚集可以通过预先形成的原纤维播种。总之，这些结果表明亨廷顿氏病的淀粉样纤维形成，就像阿尔茨海默病一样，是一种核依赖性聚合。
Huntington's disease is a progressive neurodegenerative disorder caused by a polyglutamine [poly(Q)] repeat expansion in the first exon of the huntingtin protein. Previously, we showed that N-terminal huntingtin peptides with poly(Q) tracts in the pathological range (51-122 glutamines), but not with poly(Q) tracts in the normal range (20 and 30 glutamines), form high molecular weight protein aggregates with a fibrillar or ribbon-like morphology, reminiscent of scrapie prion rods and beta-amyloid fibrils in Alzheimer's disease. Here we report that the formation of amyloidlike huntingtin aggregates in vitro not only depends on poly(Q) repeat length but also critically depends on protein concentration and time. Furthermore, the in vitro aggregation of huntingtin can be seeded by preformed fibrils. Together, these results suggest that amyloid fibrillogenesis in Huntington's disease, like in Alzheimer's disease, is a nucleation-dependent polymerization.