Oral Treatment Targeting the Unfolded Protein Response Prevents Neurodegeneration and Clinical Disease in Prion-Infected Mice
Oral Treatment Targeting the Unfolded Protein Response Prevents Neurodegeneration and Clinical Disease in Prion-Infected Mice
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DOI：
10.1126/scitranslmed.3006767
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发表时间：
2013-10-09
影响因子：
17.1
通讯作者：
Mallucci, Giovanna R.
中科院分区：
文献类型：
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作者：
Moreno, Julie A.;Halliday, Mark;Mallucci, Giovanna R.
在朊病毒疾病期间，朊病毒复制产生的错误折叠朊病毒蛋白（PrP）的增加导致控制蛋白质合成起始的未折叠蛋白反应（UPR）的分支持续过度活化。这导致翻译的持续抑制，导致关键蛋白质的丢失，从而导致突触失败和神经元死亡。我们以前曾报道，本地化的遗传操纵这一途径挽救关闭的翻译，并防止神经变性的小鼠模型朊病毒疾病，这表明，药理学抑制这一途径可能是治疗的好处。我们表明，口服治疗的激酶PERK（蛋白激酶RNA样内质网激酶），这UPR途径的关键介质的特异性抑制剂，防止UPR介导的翻译抑制和废除小鼠临床朊病毒疾病的发展，在整个小鼠大脑中观察到的神经保护。这是在临床前阶段和疾病后期出现行为体征时接受治疗的动物的情况。重要的是，该化合物作用于下游并独立于朊病毒复制的主要致病过程，尽管错误折叠的PrP持续积累，但仍然有效。这些数据表明，PERK和该途径的其他成员可能是开发抗朊病毒疾病或其他涉及UPR的神经退行性疾病药物的新治疗靶点。
During prion disease, an increase in misfolded prion protein (PrP) generated by prion replication leads to sustained overactivation of the branch of the unfolded protein response (UPR) that controls the initiation of protein synthesis. This results in persistent repression of translation, resulting in the loss of critical proteins that leads to synaptic failure and neuronal death. We have previously reported that localized genetic manipulation of this pathway rescues shutdown of translation and prevents neurodegeneration in a mouse model of prion disease, suggesting that pharmacological inhibition of this pathway might be of therapeutic benefit. We show that oral treatment with a specific inhibitor of the kinase PERK (protein kinase RNA-like endoplasmic reticulum kinase), a key mediator of this UPR pathway, prevented UPR-mediated translational repression and abrogated development of clinical prion disease in mice, with neuroprotection observed throughout the mouse brain. This was the case for animals treated both at the preclinical stage and also later in disease when behavioral signs had emerged. Critically, the compound acts downstream and independently of the primary pathogenic process of prion replication and is effective despite continuing accumulation of misfolded PrP. These data suggest that PERK, and other members of this pathway, may be new therapeutic targets for developing drugs against prion disease or other neurodegenerative diseases where the UPR has been implicated.