MRC Toxicology Unit, Hodgkin Building, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK.
Nature. 2012 May 6;485(7399):507-11. doi: 10.1038/nature11058.
The mechanisms leading to neuronal death in neurodegenerative disease are poorly understood. Many of these disorders, including Alzheimer's, Parkinson's and prion diseases, are associated with the accumulation of misfolded disease-specific proteins. The unfolded protein response is a protective cellular mechanism triggered by rising levels of misfolded proteins. One arm of this pathway results in the transient shutdown of protein translation, through phosphorylation of the α-subunit of eukaryotic translation initiation factor, eIF2. Activation of the unfolded protein response and/or increased eIF2α-P levels are seen in patients with Alzheimer's, Parkinson's and prion diseases, but how this links to neurodegeneration is unknown. Here we show that accumulation of prion protein during prion replication causes persistent translational repression of global protein synthesis by eIF2α-P, associated with synaptic failure and neuronal loss in prion-diseased mice. Further, we show that promoting translational recovery in hippocampi of prion-infected mice is neuroprotective. Overexpression of GADD34, a specific eIF2α-P phosphatase, as well as reduction of levels of prion protein by lentivirally mediated RNA interference, reduced eIF2α-P levels. As a result, both approaches restored vital translation rates during prion disease, rescuing synaptic deficits and neuronal loss, thereby significantly increasing survival. In contrast, salubrinal, an inhibitor of eIF2α-P dephosphorylation, increased eIF2α-P levels, exacerbating neurotoxicity and significantly reducing survival in prion-diseased mice. Given the prevalence of protein misfolding and activation of the unfolded protein response in several neurodegenerative diseases, our results suggest that manipulation of common pathways such as translational control, rather than disease-specific approaches, may lead to new therapies preventing synaptic failure and neuronal loss across the spectrum of these disorders.
导致神经退行性疾病神经元死亡的机制尚未完全阐明。许多此类疾病，包括阿尔茨海默病、帕金森病和朊病毒病，都与特定疾病相关的错误折叠蛋白的积累有关。未折叠蛋白反应是一种由错误折叠蛋白水平升高引发的细胞保护机制。该途径的一个分支导致通过真核翻译起始因子α亚基（eIF2）的磷酸化，导致蛋白质翻译短暂关闭。在阿尔茨海默病、帕金森病和朊病毒病患者中可见未折叠蛋白反应的激活和/或 eIF2α-P 水平升高，但这与神经退行性变的关系尚不清楚。在这里，我们表明朊病毒复制过程中朊病毒蛋白的积累会导致 eIF2α-P 引起的全局蛋白质合成持续受到抑制，从而导致朊病毒病小鼠中的突触功能障碍和神经元丢失。此外，我们还表明，促进朊病毒感染小鼠海马体中的翻译恢复具有神经保护作用。过表达 GADD34，一种特定的 eIF2α-P 磷酸酶，以及通过慢病毒介导的 RNA 干扰降低朊病毒蛋白水平，可降低 eIF2α-P 水平。结果，这两种方法都在朊病毒病过程中恢复了重要的翻译速率，挽救了突触缺陷和神经元丢失，从而显著提高了存活率。相比之下，salubrinal，一种 eIF2α-P 去磷酸化抑制剂，增加了 eIF2α-P 水平，加重了神经毒性，并显著降低了朊病毒病小鼠的存活率。鉴于在几种神经退行性疾病中普遍存在蛋白质错误折叠和未折叠蛋白反应的激活，我们的结果表明，操纵常见途径，如翻译控制，而不是针对特定疾病的方法，可能会为预防这些疾病谱中突触功能障碍和神经元丢失提供新的治疗方法。
