Length of huntingtin and its polyglutamine tract influences localization and frequency of intracellular aggregates
Length of huntingtin and its polyglutamine tract influences localization and frequency of intracellular aggregates
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DOI：
10.1038/ng0298-150
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发表时间：
1998-02-01
期刊：
影响因子：
30.8
通讯作者：
Hayden, MR
中科院分区：
文献类型：
--
作者：
Martindale, D;Hackam, A;Hayden, MR
目前尚不清楚聚谷氨酰胺扩增如何与亨廷顿病（HD）的发病机制相关。在这里。我们提供的证据表明，聚谷氨酰胺膨胀导致形成大的细胞内聚集体在体外和体内。在体外，这些含有亨廷顿蛋白的聚集体破坏正常的细胞结构，并随着聚谷氨酰胺的长度增加频率。在核苷酸1955处截断的亨廷顿蛋白，靠近caspase-3切割位点，比全长亨廷顿蛋白更容易形成核周聚集体，并增加细胞在凋亡刺激后死亡的易感性。亨廷顿蛋白进一步截断为核苷酸436导致核内和核周聚集。对于给定的蛋白质大小，增加聚谷氨酰胺长度与增加细胞毒性有关。无症状的转基因小鼠表达全长亨廷顿蛋白和138个多谷氨酰胺在神经元中形成完全的核周围聚集体。这些数据支持以下假设：突变的亨廷顿蛋白的蛋白水解裂解导致聚集体的发展，从而损害细胞活力，并且它们的定位受蛋白质长度的影响。
It is unclear how polyglutamine expansion is associated with the pathogenesis of Huntington disease (HD). Here. we provide evidence that polyglutamine expansion leads to the formation of large intracellular aggregates in vitro and in vivo. In vitro these huntingtin-containing aggregates disrupt normal cellular architecture and increase in frequency with polyglutamine length. Huntingtin truncated at nucleotide 1955, close to the caspase-3 cleavage site, forms perinuclear aggregates more readily than full-length huntingtin and increases the susceptibility of cells to death following apoptotic stimuli. Further truncation of huntingtin to nucleotide 436 results in both intranuclear and perinuclear aggregates. For a given protein size, increasing polyglutamine length is associated with increased cellular toxicity. Asymptomatic transgenic mice expressing full-length huntingtin with 138 polyglutamines form exclusively perinuclear aggregates in neurons. These data support the hypothesis that proteolytic cleavage of mutant huntingtin leads to the development of aggregates which compromise cell viability, and that their localization is influenced by protein length.