PERK inhibition prevents tau-mediated neurodegeneration in a mouse model of frontotemporal dementia.
PERK inhibition prevents tau-mediated neurodegeneration in a mouse model of frontotemporal dementia.
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DOI：
10.1007/s00401-015-1487-z
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发表时间：
2015-11
影响因子：
12.7
通讯作者：
Mallucci GR
中科院分区：
文献类型：
--
作者：
Radford H;Moreno JA;Verity N;Halliday M;Mallucci GR
未折叠蛋白反应（UPR）的PERK-eIF 2 α分支介导翻译的短暂关闭，以响应内质网中错误折叠蛋白水平的升高。PERK和eIF 2 α激活在神经退行性疾病（包括阿尔茨海默病、tau蛋白病和朊病毒疾病）患者的尸检分析中越来越多地被认识到。这些疾病的特征都是错误折叠的疾病特异性蛋白质在脑中的积累，与神经元丢失的特定模式相关，但UPR激活在其发病机制中的作用尚不清楚。在朊病毒病小鼠中，PERK-P/eIF 2 α-P信号转导的过度激活导致整体蛋白质合成的持续减少，导致突触失败、神经元损失和临床疾病。重要的是，通过抑制PERK-eIF 2 α通路（遗传和非遗传）恢复重要的神经元蛋白质合成速率，可防止错误折叠的朊病毒蛋白积累下游的朊病毒神经变性。在这里，我们表明PERK-eIF 2 α介导的翻译失败是导致额颞叶痴呆小鼠模型中神经元损失的关键过程，其中错误折叠的蛋白质是突变tau的一种形式。过度表达P301 L tau突变的rTg 4510小鼠在6个月龄时表现出PERK信号传导失调和蛋白质合成的持续抑制，与神经变性的发作相关。从这个时间点开始，在突变型tau表达小鼠中用PERK抑制剂GSK 2606414治疗恢复蛋白质合成速率，防止进一步的神经元损失，减少脑萎缩并消除临床体征的出现。此外，我们发现PERK-eIF 2 α激活也有助于rTg 4510小鼠中tau的病理性磷酸化，并且PERK抑制剂治疗降低了磷酸化tau的水平，提供了第二种保护机制。这些数据支持UPR介导的翻译失败作为蛋白质错误折叠疾病（包括tau蛋白病）的一般致病机制，可以成功地靶向预防神经变性。
The PERK-eIF2α branch of the Unfolded Protein Response (UPR) mediates the transient shutdown of translation in response to rising levels of misfolded proteins in the endoplasmic reticulum. PERK and eIF2α activation are increasingly recognised in postmortem analyses of patients with neurodegenerative disorders, including Alzheimer’s disease, the tauopathies and prion disorders. These are all characterised by the accumulation of misfolded disease-specific proteins in the brain in association with specific patterns of neuronal loss, but the role of UPR activation in their pathogenesis is unclear. In prion-diseased mice, overactivation of PERK-P/eIF2α-P signalling results in the sustained reduction in global protein synthesis, leading to synaptic failure, neuronal loss and clinical disease. Critically, restoring vital neuronal protein synthesis rates by inhibiting the PERK-eIF2α pathway, both genetically and pharmacologically, prevents prion neurodegeneration downstream of misfolded prion protein accumulation. Here we show that PERK-eIF2α-mediated translational failure is a key process leading to neuronal loss in a mouse model of frontotemporal dementia, where the misfolded protein is a form of mutant tau. rTg4510 mice, which overexpress the P301L tau mutation, show dysregulated PERK signalling and sustained repression of protein synthesis by 6 months of age, associated with onset of neurodegeneration. Treatment with the PERK inhibitor, GSK2606414, from this time point in mutant tau-expressing mice restores protein synthesis rates, protecting against further neuronal loss, reducing brain atrophy and abrogating the appearance of clinical signs. Further, we show that PERK-eIF2α activation also contributes to the pathological phosphorylation of tau in rTg4510 mice, and that levels of phospho-tau are lowered by PERK inhibitor treatment, providing a second mechanism of protection. The data support UPR-mediated translational failure as a generic pathogenic mechanism in protein-misfolding disorders, including tauopathies, that can be successfully targeted for prevention of neurodegeneration.