Small N-terminal mutant huntingtin fragments, but not wild type, are mainly present in monomeric form: Implications for pathogenesis
Small N-terminal mutant huntingtin fragments, but not wild type, are mainly present in monomeric form: Implications for pathogenesis
复制标题
DOI：
10.1016/j.expneurol.2005.11.008
复制
发表时间：
2006-06-01
影响因子：
5.3
通讯作者：
Dorsman, Josephine C.
中科院分区：
文献类型：
--
作者：
Cong, Shu-Yan;Pepers, Barry A.;Dorsman, Josephine C.
亨廷顿蛋白的N-末端片段含有扩展的多聚谷氨酰胺片段，在亨廷顿病的分子发病机制中起重要作用。它们最终在不溶性蛋白质聚集体中的积累构成了亨廷顿病的重要病理学标志。我们报告可溶性野生型和突变N-末端亨廷顿蛋白片段的系统生化比较研究。结果显示，可溶性野生型外显子1片段主要存在于分子大小类似于300 kDa的较高分子量复合物中，而它们的突变体对应物主要以它们的单体形式存在。相比之下，较长的N-末端片段对应于由胱天蛋白酶切割产生的肽不显示这些差异特性。这些研究结果表明，特别是增加量的单体形式的小N-末端突变亨廷顿蛋白片段可以促进异常的相互作用，通过多聚谷氨酰胺拉伸本身和与其他蛋白质，从而有助于分子发病机制。(c)2005年爱思唯尔公司All rights reserved.
N-terminal fragments of huntingtin containing an expanded polyglutamine stretch play an important role in the molecular pathogenesis of Huntington's disease. Their ultimate accumulation in insoluble protein aggregates constitutes an important pathological hallmark of Huntington's disease. We report on systematic biochemical comparison studies of soluble wild type and mutant N-terminal huntingtin fragments. The results show that soluble wild type exon 1 fragments are predominantly present in higher molecular weight complexes with a molecular size of similar to 300 kDa, while their mutant counterparts are mainly present in their monomeric form. In contrast, longer N-terminal fragments corresponding to peptides produced by caspase cleavage do not display these differential properties. These findings suggest that especially an increased amount of monomeric form of small N-terminal mutant huntingtin fragments may facilitate aberrant interactions both with itself via the polyglutamine stretch and with other proteins and thereby contribute to molecular pathogenesis. (c) 2005 Elsevier Inc. All rights reserved.