Sustained translational repression by eIF2α-P mediates prion neurodegeneration.
Sustained translational repression by eIF2α-P mediates prion neurodegeneration.
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DOI：
10.1038/nature11058
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发表时间：
2012-05-06
期刊：
影响因子：
64.8
通讯作者：
Mallucci, Giovanna R.
中科院分区：
文献类型：
--
作者：
Moreno, Julie A.;Radford, Helois;Peretti, Diego;Steinert, Joern R.;Verity, Nicholas;Martin, Maria Guerra;Halliday, Mark;Morgan, Jason;Dinsdale, David;Ortori, Catherine A.;Barrett, David A.;Tsaytler, Pavel;Bertolotti, Anne;Willis, Anne E.;Bushell, Martin;Mallucci, Giovanna R.
导致神经退行性疾病中神经元死亡的机制知之甚少。这些疾病中的许多，包括阿尔茨海默病（AD）、帕金森病（PD）和朊病毒疾病，与错误折叠的疾病特异性蛋白质的积累有关。未折叠蛋白反应（UPR）是一种由错误折叠蛋白水平升高引发的保护性细胞机制。该途径的一个分支通过真核翻译起始因子eIF 2 α α α亚基的磷酸化导致蛋白质翻译的瞬时关闭。UPR激活和/或eIF 2 α-P水平升高见于AD、PD和朊病毒病患者，但其与神经变性的联系尚不清楚。我们发现朊病毒复制过程中朊病毒蛋白（PrP）的积累导致eIF 2 α-P对整体蛋白合成的持续翻译抑制，与朊病毒病小鼠的突触失效和神经元丢失相关。此外，我们表明，促进朊病毒感染小鼠的大脑中的翻译恢复是神经保护性的。过表达GADD 34（一种特异性eIF 2 α-P磷酸酶）以及通过慢病毒介导的RNAi降低PrP水平可降低eIF 2 α-P水平。结果，这两种方法都恢复了朊病毒疾病期间的重要翻译速率，挽救了突触缺陷和神经元损失，从而显着提高了存活率。相反，salubrinal，eIF 2 α-P去磷酸化的抑制剂，增加eIF 2 α-P水平，加剧神经毒性，并显着降低朊病毒病小鼠的生存率。考虑到蛋白质错误折叠和UPR激活在几种神经退行性疾病中的普遍性，我们的研究结果表明，操纵常见的途径，如翻译控制，而不是疾病特异性方法，可能会导致新的治疗方法，预防突触失败和神经元损失在这些疾病的频谱。
The mechanisms leading to neuronal death in neurodegenerative disease are poorly understood. Many of these disorders, including Alzheimer’s (AD), Parkinson’s (PD) and prion diseases, are associated with the accumulation of misfolded disease-specific proteins. The unfolded protein response (UPR) 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 alpha subunit of eukaryotic translation initiation factor, eIF2α. UPR activation and/or increased eIF2α–P levels are seen in patients with AD, PD and prion disease , but how this links to neurodegeneration is unknown. Here we show that accumulation of prion protein (PrP) 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. Over-expression of GADD34, a specific eIF2α–P phosphatase, as well as reduction of PrP levels by lentivirally-mediated RNAi, reduced eIF2α–P levels. As a result, both approaches restored vital translation rates during prion disease, rescuing synaptic deficits and neuronal loss, and 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 UPR activation 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.
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