Hsp105α suppresses the aggregation of truncated androgen receptor with expanded CAG repeats and cell toxicity
Hsp105α suppresses the aggregation of truncated androgen receptor with expanded CAG repeats and cell toxicity
复制标题
DOI：
10.1074/jbc.m302975200
复制
发表时间：
2003-07-04
影响因子：
4.8
通讯作者：
Hatayama, T
中科院分区：
文献类型：
--
作者：
Ishihara, K;Yamagishi, N;Hatayama, T
脊髓延髓肌萎缩症（SBMA）是由雄激素受体（AR）中多聚谷氨酰胺束扩张引起的神经退行性疾病。含有扩增的多聚谷氨酰胺束的AR的N-末端片段在细胞质和/或细胞核中聚集并诱导细胞死亡。一些分子伴侣如Hsp 40和Hsp 70已被鉴定为神经元细胞中多聚谷氨酰胺聚集和/或细胞死亡的重要调节剂。最近，Hsp 105 α在哺乳动物脑中以特别高的水平表达，已被证明可以抑制神经元细胞的凋亡，并防止由热休克引起的蛋白质聚集。然而，其在聚谷氨酰胺介导的细胞死亡和毒性中的作用尚未研究。在本研究中，我们研究了热休克蛋白105 α的聚集和细胞毒性所造成的多聚谷氨酰胺道使用SBMA的细胞模型的扩展的影响。含有扩增的多聚谷氨酰胺束的截短的AR（tAR）的瞬时表达导致在COS-7和SK-N-SH细胞中形成聚集体，并且伴随着在具有核聚集体的细胞中的凋亡。当Hsp 105 α与tAR 97在细胞中过表达时，Hsp 105 α共定位于tAR 97的聚集体，并且由多聚谷氨酰胺束扩张引起的聚集和细胞毒性显著降低。热休克蛋白105 α的β-折叠和β-螺旋结构域，而不是ATP酶结构域，是抑制体内和体外聚集体形成所必需的。此外，发现Hsp 105 α定位于SBMA患者和转基因小鼠组织中由含有扩展的多聚谷氨酰胺束的AR形成的核包涵体中。这些结果表明，过度表达Hsp 105 α抑制细胞死亡所造成的扩张的多聚谷氨酰胺道没有伴侣活性，和Hsp 105 α在大脑中的重要结构域的表达增强可能提供了一个有效的治疗方法CAG重复疾病。
Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disorder caused by the expansion of a polyglutamine tract in the androgen receptor (AR). The N-terminal fragment of AR containing the expanded polyglutamine tract aggregates in cytoplasm and/or in nucleus and induces cell death. Some chaperones such as Hsp40 and Hsp70 have been identified as important regulators of polyglutamine aggregation and/or cell death in neuronal cells. Recently, Hsp105alpha, expressed at especially high levels in mammalian brain, has been shown to suppress apoptosis in neuronal cells and prevent the aggregation of protein caused by heat shock in vitro. However, its role in polyglutamine-mediated cell death and toxicity has not been studied. In the present study, we examined the effects of Hsp105alpha on the aggregation and cell toxicity caused by expansion of the polyglutamine tract using a cellular model of SBMA. The transient expression of truncated ARs (tARs) containing an expanded polyglutamine tract caused aggregates to form in COS-7 and SK-N-SH cells and concomitantly apoptosis in the cells with the nuclear aggregates. When Hsp105alpha was overexpressed with tAR97 in the cells, Hsp105alpha was colocalized to aggregates of tAR97, and the aggregation and cell toxicity caused by expansion of the polyglutamine tract were markedly reduced. Both beta-sheet and beta-helix domains, but not the ATPase domain, of Hsp105alpha were necessary to suppress the formation of aggregates in vivo and in vitro. Furthermore, Hsp105alpha was found to localize in nuclear inclusions formed by ARs containing an expanded polyglutamine tract in tissues of patients and transgenic mice with SBMA. These findings suggest that overexpression of Hsp105alpha suppresses cell death caused by expansion of the polyglutamine tract without chaperone activity, and the enhanced expression of the essential domains of Hsp105alpha in brain may provide an effective therapeutic approach for CAG repeat diseases.