Heat shock transcription factor 1-activating compounds suppress polyglutamine-induced neurodegeneration through induction of multiple molecular chaperones
Heat shock transcription factor 1-activating compounds suppress polyglutamine-induced neurodegeneration through induction of multiple molecular chaperones
复制标题
DOI：
10.1074/jbc.m710521200
复制
发表时间：
2008-09-19
影响因子：
4.8
通讯作者：
Toda, Tatsushi
中科院分区：
文献类型：
--
作者：
Fujikake, Nobuhiro;Nagai, Yoshitaka;Toda, Tatsushi
许多神经退行性疾病，包括阿尔茨海默病，帕金森病和多聚谷氨酰胺（polyQ）疾病被认为是由蛋白质错误折叠引起的。polyQ疾病，包括亨廷顿病和脊髓小脑共济失调（SCA），是由致病蛋白中polyQ伸展的异常扩张引起的，这触发了这些蛋白的错误折叠，导致它们在受影响的神经元中沉积为包涵体。尽管分子伴侣的遗传表达已显示抑制polyQ蛋白错误折叠和神经变性，但为了开发治疗，理想的是通过化学施用诱导内源性分子伴侣。在这项研究中，我们评估了热休克转录因子1（HSF 1）激活化合物，诱导多个分子伴侣，对polyQ诱导的神经退行性变在体内的治疗效果。我们发现口服17-（烯丙基氨基）-17-去甲氧基格尔德霉素（17-AAG）可显著抑制果蝇SCA模型的复眼变性和包涵体形成。17-AAG还显著地挽救了SCA模型的致死率（74.1%挽救）并抑制了亨廷顿病模型中的神经变性（46.3%挽救），表明17-AAG对各种polyQ疾病广泛有效。17-AAG以剂量依赖性方式诱导Hsp 70、Hsp 40和Hsp 90的表达，并且表达水平与其治疗效果相关。此外，HSF 1的敲低消除了分子伴侣的诱导和17-AAG的治疗作用，表明其治疗作用依赖于HSF 1的活化。我们的研究表明，通过17-AAG治疗诱导多个分子伴侣是一种有前途的治疗方法，用于广泛的polyQ疾病和可能的其他神经退行性疾病。
Many neurodegenerative diseases including Alzheimer, Parkinson, and polyglutamine ( polyQ) diseases are thought to be caused by protein misfolding. The polyQ diseases, including Huntington disease and spinocerebellar ataxias (SCAs), are caused by abnormal expansions of the polyQ stretch in disease-causing proteins, which trigger misfolding of these proteins, resulting in their deposition as inclusion bodies in affected neurons. Although genetic expression of molecular chaperones has been shown to suppress polyQ protein misfolding and neurodegeneration, toward developing a therapy, it is ideal to induce endogenous molecular chaperones by chemical administration. In this study, we assessed the therapeutic effects of heat shock transcription factor 1 ( HSF1)-activating compounds, which induce multiple molecular chaperones, on polyQ-induced neurodegeneration in vivo. We found that oral administration of 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) markedly suppresses compound eye degeneration and inclusion body formation in a Drosophila model of SCA. 17-AAG also dramatically rescued the lethality of the SCA model (74.1% rescue) and suppressed neurodegeneration in a Huntington disease model (46.3% rescue), indicating that 17-AAG is widely effective against various polyQ diseases. 17-AAG induced Hsp70, Hsp40, and Hsp90 expression in a dose-dependent manner, and the expression levels correlated with its therapeutic effects. Furthermore, knockdown of HSF1 abolished the induction of molecular chaperones and the therapeutic effect of 17-AAG, indicating that its therapeutic effects depend on HSF1 activation. Our study indicates that induction of multiple molecular chaperones by 17-AAG treatment is a promising therapeutic approach for a wide range of polyQ diseases and possibly other neurodegenerative diseases.