Active HSF1 significantly suppresses polyglutamine aggregate formation in cellular and mouse models
Active HSF1 significantly suppresses polyglutamine aggregate formation in cellular and mouse models
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DOI：
10.1074/jbc.m506288200
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发表时间：
2005-10-14
影响因子：
4.8
通讯作者：
Nakai, A
中科院分区：
文献类型：
--
作者：
Fujimoto, M;Takaki, E;Nakai, A
多聚谷氨酰胺病是一种遗传性神经退行性疾病，其特征是具有扩展的多聚谷氨酰胺重复序列的蛋白质的错误折叠和聚集。由于某些热休克蛋白（Hsp）的过表达抑制了多聚谷氨酰胺聚集和细胞死亡，因此认为Hsp的联合过表达将更有效地抑制这种现象。在这里，我们研究了热休克转录因子1（HSF 1）的活性形式，它诱导一组热休克蛋白，对多聚谷氨酰胺包涵体的形成和疾病进展的影响。我们发现，活性HSF 1抑制多聚谷氨酰胺包涵体的形成更显着比任何组合的热休克蛋白在培养细胞中，可能通过调节未知基因的表达，以及主要的热休克蛋白。我们将R6/2亨廷顿病小鼠与表达活性HSF 1（HSF 1 Tg）的转基因小鼠杂交。骨骼肌的分析表明，在R6/2/HSF 1 Tg小鼠中，多聚谷氨酰胺包涵体的形成和其体重减轻得到改善。出乎意料的是，R6/2/HSF 1 Tg小鼠的寿命显著提高，尽管活性HSF 1在大脑中不表达。这些结果表明，活性HSF 1在体内和体外对聚谷氨酰胺聚集体的形成具有强烈的抑制作用。
Polyglutamine diseases are inherited neurodegenerative diseases characterized by misfolding and aggregation of proteins possessing expanded polyglutamine repeats. As overexpression of some heat shock protein (Hsp) suppresses polyglutamine aggregates and cell death, it is assumed that combined overexpression of Hsps will suppress that more effectively. Here, we examined the impact of active forms of heat shock transcription factor 1 (HSF1), which induces a set of Hsps, on polyglutamine inclusion formation and disease progression. We found that active HSF1 suppressed polyglutamine inclusion formation more significantly than any combination of Hsps in culture cells, possibly by regulating expression of unknown genes, as well as major Hsps. We crossed R6/2 Huntington disease mice with transgenic mice expressing an active HSF1 (HSF1Tg). Analysis of the skeletal muscle revealed that the polyglutamine inclusion formation and its weight loss were improved in R6/2/HSF1Tg mice. Unexpectedly, the life span of R6/2/HSF1Tg mice was significantly improved, although active HSF1 is not expressed in the brain. These results indicated that active HSF1 has a strong inhibitory effect on polyglutamine aggregate formation in vivo and in vitro.