The disulfide isomerase Grp58 is a protective factor against prion neurotoxicity
The disulfide isomerase Grp58 is a protective factor against prion neurotoxicity
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DOI：
10.1523/jneurosci.4090-04.2005
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发表时间：
2005-03-16
影响因子：
5.3
通讯作者：
Soto, C
中科院分区：
文献类型：
--
作者：
Hetz, C;Russelakis-Carneiro, M;Soto, C
朊病毒病是一种以广泛的神经元凋亡和错误折叠的朊蛋白（PrPSC）积累为特征的传染性神经退行性疾病。最近的报道表明，PrPSC诱导神经元凋亡通过激活内质网（ER）应激途径和激活ER驻留caspase-12。在这里，我们研究朊病毒复制和诱导ER应激在不同阶段的疾病在小鼠瘙痒症模型之间的关系。观察到的第一个变化包括葡萄糖调节蛋白Grp 58的ER伴侣的上调，这是在症状前阶段检测到的，紧随PrPSC的形成。Grp 58表达的增加与PrPSC在不同脑区疾病的所有阶段的积累相关，表明这种伴侣蛋白可能在朊病毒感染的细胞反应中起重要作用。事实上，使用N2 a神经母细胞瘤细胞的体外研究表明，用小干扰RNA抑制Grp 58表达导致PrPSC毒性的显著增强。相反，Grp 58的过表达保护细胞免受PrPSC毒性，并降低半胱天冬酶-12活化的速率。Grp 58和PrP通过免疫共沉淀相互作用，在感染羊瘙痒病朊病毒的细胞中观察到更高的相互作用。我们的数据表明，Grp 58的表达是朊病毒复制的早期细胞反应，作为朊病毒神经毒性的神经保护因子。我们的研究结果表明，针对Grp 58相互作用可能有开发新的治疗和早期诊断朊病毒疾病的策略的应用。
Prion diseases are transmissible neurodegenerative disorders characterized by extensive neuronal apoptosis and accumulation of misfolded prion protein (PrPSC). Recent reports indicate that PrPSC induces neuronal apoptosis via activation of the endoplasmic reticulum (ER) stress pathway and activation of the ER resident caspase-12. Here, we investigate the relationship between prion replication and induction of ER stress during different stages of the disease in a murine scrapie model. The first alteration observed consists of the upregulation of the ER chaperone of the glucose-regulated protein Grp58, which was detected during the presymptomatic phase and followed closely the formation of PrPSC. An increase in Grp58 expression correlated with PrPSC accumulation at all stages of the disease in different brain areas, suggesting that this chaperone may play an important role in the cellular response to prion infection. Indeed, in vitro studies using N2a neuroblastoma cells demonstrated that inhibition of Grp58 expression with small interfering RNA led to a significant enhancement of PrPSC toxicity. Conversely, overexpression of Grp58 protected cells against PrPSC toxicity and decreased the rate of caspase-12 activation. Grp58 and PrP were shown to interact by coimmunoprecipitation, observing a higher interaction in cells infected with scrapie prions. Our data indicate that expression of Grp58 is an early cellular response to prion replication, acting as a neuroprotective factor against prion neurotoxicity. Our findings suggest that targeting Grp58 interaction may have applications for developing novel strategies for treatment and early diagnosis of prion diseases.