Cross-Seeding Fibrillation of Q/N-Rich Proteins Offers New Pathomechanism of Polyglutamine Diseases
Cross-Seeding Fibrillation of Q/N-Rich Proteins Offers New Pathomechanism of Polyglutamine Diseases
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DOI：
10.1523/jneurosci.0783-09.2009
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发表时间：
2009-04-22
影响因子：
5.3
通讯作者：
Nukina, Nobuyuki
中科院分区：
文献类型：
--
作者：
Furukawa, Yoshiaki;Kaneko, Kumi;Nukina, Nobuyuki
亨廷顿氏病（HD）的病理特征是细胞内包涵体含有亨廷顿蛋白（Htt），其多聚谷氨酰胺束延长。突变体Htt的聚集导致蛋白-蛋白相互作用异常，聚集相互作用蛋白（AIPs）的功能失调被认为是HD的一种病理机制。尽管如此，Htt聚集隔离AIPs的分子机制仍然未知。我们注意到rna结合蛋白TIA-1作为AIPs的模型含有一个Q/ n丰富的序列，并提示体外和体内Htt纤维聚集体作为诱导TIA-1不溶性颤动的结构模板。Htt聚集体的这种交叉播种活性也可能抑制TIA-1的生理功能。因此，我们提出Htt聚集体作为富Q/ n AIPs的交叉种子纤颤的细胞内枢纽，交叉种子反应是引起多聚谷氨酰胺疾病多种病理的分子起源。
A pathological hallmark of the Huntington's disease (HD) is intracellular inclusions containing a huntingtin (Htt) protein with an elongated polyglutamine tract. Aggregation of mutant Htt causes abnormal protein-protein interactions, and the functional dysregulation of aggregate-interacting proteins (AIPs) has been proposed as a pathomechanism of HD. Despite this, a molecular mechanism remains unknown how Htt aggregates sequester AIPs. We note an RNA-binding protein, TIA-1, as a model of AIPs containing a Q/N-rich sequence and suggest that in vitro and in vivo Htt fibrillar aggregates function as a structural template for inducing insoluble fibrillation of TIA-1. It is also plausible that such a cross-seeding activity of Htt aggregates represses the physiological function of TIA-1. We thus propose that Htt aggregates act as an intracellular hub for the cross-seeded fibrillation of Q/N-rich AIPs and that a cross-seeding reaction is a molecular origin to cause diverse pathologies in a polyglutamine disease.