Partial restoration of protein synthesis rates by the small molecule ISRIB prevents neurodegeneration without pancreatic toxicity.
Partial restoration of protein synthesis rates by the small molecule ISRIB prevents neurodegeneration without pancreatic toxicity.
复制标题
DOI：
10.1038/cddis.2015.49
复制
发表时间：
2015-03-05
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
内质网（ER）内蛋白质错误折叠激活未折叠蛋白反应（UPR）的PERK分支，导致蛋白质合成的瞬时抑制，这是由真核起始因子2 α（eIF 2 α）的α亚基磷酸化介导的。这是在面对ER应激时维持蛋白质稳态的更广泛的综合生理反应的一部分，ER应激的失调越来越多地与广泛的疾病，特别是神经退行性疾病相关。在朊病毒病小鼠中，持续高水平的eIF 2 α引起持续的翻译抑制，导致关键蛋白的灾难性减少，导致突触失败和神经元丢失。我们先前表明，使用PERK抑制剂GSK 2606414恢复整体蛋白质合成具有深刻的神经保护作用，可预防朊病毒感染小鼠的临床疾病。然而，这是以对分泌组织的毒性为代价的，其中UPR活化对健康功能至关重要。在这里，我们表明，药理学调节eIF 2 α-P介导的翻译抑制可以实现产生神经保护，而没有胰腺毒性。我们发现，用小分子ISRIB治疗，恢复eIF 2 α下游的翻译，在朊病毒病小鼠中赋予神经保护作用，而对胰腺没有不良影响。重要的是，ISRIB治疗仅导致整体翻译速率的部分恢复，而GSK 2606414则完全恢复了蛋白质合成。ISRIB可能为神经元存活提供足够的蛋白质合成速率，同时在分泌组织中允许一些残留的保护性UPR功能。因此，微调UPR抑制的程度和随后的翻译去阻遏将神经保护作用与胰腺毒性解偶联。这些数据支持这种方法的追求，为目前无法治愈的一系列神经退行性疾病开发新的治疗方法。
Activation of the PERK branch of the unfolded protein response (UPR) in response to protein misfolding within the endoplasmic reticulum (ER) results in the transient repression of protein synthesis, mediated by the phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF2α). This is part of a wider integrated physiological response to maintain proteostasis in the face of ER stress, the dysregulation of which is increasingly associated with a wide range of diseases, particularly neurodegenerative disorders. In prion-diseased mice, persistently high levels of eIF2α cause sustained translational repression leading to catastrophic reduction of critical proteins, resulting in synaptic failure and neuronal loss. We previously showed that restoration of global protein synthesis using the PERK inhibitor GSK2606414 was profoundly neuroprotective, preventing clinical disease in prion-infected mice. However, this occured at the cost of toxicity to secretory tissue, where UPR activation is essential to healthy functioning. Here we show that pharmacological modulation of eIF2α-P-mediated translational inhibition can be achieved to produce neuroprotection without pancreatic toxicity. We found that treatment with the small molecule ISRIB, which restores translation downstream of eIF2α, conferred neuroprotection in prion-diseased mice without adverse effects on the pancreas. Critically, ISRIB treatment resulted in only partial restoration of global translation rates, as compared with the complete restoration of protein synthesis seen with GSK2606414. ISRIB likely provides sufficient rates of protein synthesis for neuronal survival, while allowing some residual protective UPR function in secretory tissue. Thus, fine-tuning the extent of UPR inhibition and subsequent translational de-repression uncouples neuroprotective effects from pancreatic toxicity. The data support the pursuit of this approach to develop new treatments for a range of neurodegenerative disorders that are currently incurable.
登录
查看更多内容
影响因子：
9
作者：
通讯作者：
--
影响因子：
30.8
作者：
Kim, Hyung-Jun;Raphael, Alya R.;LaDow, Eva S.;McGurk, Leeanne;Weber, Ross A.;Trojanowski, John Q.;Lee, Virginia M-Y;Finkbeiner, Steven;Gitler, Aaron D.;Bonini, Nancy M.
通讯作者：
Bonini, Nancy M.
影响因子：
64.8
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.
通讯作者：
Mallucci, Giovanna R.
影响因子：
4.2
作者：
Devi L;Ohno M
通讯作者：
Ohno M
影响因子：
16.2
作者：
Mallucci, Giovanna R.;White, Melanie D.;Collinge, John
通讯作者：
Collinge, John