Increased aggregation of polyleucine compared with that of polyglutamine in dentatorubral-pallidoluysian atrophy protein.
Increased aggregation of polyleucine compared with that of polyglutamine in dentatorubral-pallidoluysian atrophy protein.
复制标题
与齿状红核-苍白球路易体萎缩蛋白中的聚谷氨酰胺相比，聚亮氨酸的聚集增加。
DOI：
10.1016/j.neulet.2013.07.043
复制
发表时间：
2013
影响因子：
2.5
通讯作者：
Yazawa I.
中科院分区：
文献类型：
--
作者：
Suzuki Y;Jin C;Yazawa I.
多聚谷氨酰胺（polyQ）疾病是由其相关基因CAG三核苷酸重复扩增引起的。虽然具有多q扩增的基因产物经过构象变化在神经元中聚集，但包涵体与神经毒性之间的关系尚不清楚。齿状网膜-白斑萎缩症（DRPLA）是一种多q疾病，DRPLA蛋白，也称为atrophin-1 (ATN1)，携带扩张的多q束。为了研究扩大的多q束如何影响ATN1的聚集和定位，我们比较了ATN1与多q束的聚集和ATN1与聚亮氨酸（polyL）束的聚集。在COS-7细胞中，polyL-ATN1比相同重复大小的polyQ-ATN1触发更多的聚集。免疫细胞化学和生化研究表明，用polyL取代polyQ通道改变了ATN1的定位，导致polyL-ATN1在细胞质中保留。尽管定位发生了变化，polyL-ATN1和polyQ-ATN1表现出相似的重复序列长度依赖性毒性。这些结果表明，ATN1中扩大的多q重复序列可能通过蛋白质聚集和细胞内定位的改变而导致神经退行性变。
Polyglutamine (polyQ) diseases result from expansion of CAG trinucleotide repeats in their responsible genes. Although gene products with polyQ expansions undergo conformational changes to aggregate in neurons, the relationship between inclusions and neurotoxicity remains unclear. Dentatorubral-pallidoluysian atrophy (DRPLA) is a polyQ disease, and DRPLA protein, also known as atrophin-1 (ATN1), carries an expanded polyQ tract. To investigate how an expanded polyQ tract influences ATN1 aggregation and localization, we compared the aggregation of ATN1 with a polyQ tract to that of ATN1 with a polyleucine (polyL) tract. In COS-7 cells, polyL-ATN1 triggered more aggregation than polyQ-ATN1 of similar repeat sizes. Immunocytochemical and biochemical studies revealed that replacement of the polyQ tract with polyL alters ATN1 localization, leading to retention of polyL-ATN1 in the cytoplasm. Despite this change in localization, polyL-ATN1 and polyQ-ATN1 demonstrate comparable repeat length dependent toxicity. These results suggest that expanded polyQ repeats in ATN1 may contribute to neurodegeneration via alterations in both protein aggregation and intracellular localization.