PERK inhibition as a therapeutic approach for Alzheimer's disease

内质网(ER)折叠能力障碍提示 称为内质网应激的细胞状态。神经退行性疾病诱发内质网应激 包括阿尔茨海默病(AD)。PERK是一种主要的内质网应激敏感蛋白 它可以被内质网腔结构域中的错误折叠蛋白激活，从而启动内质网应激。 越来越多的证据表明，PERK的激活与 与AD的发病机制有关。PERK激活可导致BACE1的过度表达 淀粉样蛋白β(Aβ)斑块的沉积和tau蛋白的磷酸化。延长了 PERK的激活也可能通过细胞凋亡导致神经元丢失。来自AD动物的可靠数据 模型表明，PERK的耗尽或抑制可能表现出大量的 保护神经，减少AD大脑中与AD相关的斑块的数量。然而， 现有的PERK抑制剂是三磷酸腺苷类似物，具有高毒性和低毒性。 体内特异性。我们的数据支持错误折叠的蛋白质可以直接 与PERK相互作用，激活PERK信号通路。我们建议将小说 PERK的抑制剂，可以阻断PERK管腔结构域和 高通量筛选错折叠蛋白质。这些小分子抑制剂可能 通过减弱内质网应激信号来代表治疗AD的新方法。我们有 确定了Perk鲁米那结构域及其多肽底物的复杂晶体结构， 这使得我们可以通过基于结构的药物设计来优化已识别的抑制剂。

Disturbance in the folding capacity of endoplasmic reticulum (ER) prompts a cellular condition known as ER stress. ER stress is induced in neurodegenerative diseases including Alzheimer’s disease (AD). PERK is one of the major ER stress sensor proteins which can be activated by misfolded protein in ER luminal domain to initiate the ER stress. Accumulating evidences have demonstrated that the PERK activation is closely associated with the pathogenesis of AD. PERK activation can lead to overexpression of BACE1, the deposition of amyloid β (Aβ) plaques and the phosphorylation of tau protein. Prolonged PERK activation may also cause the neuronal loss by apoptosis. Solid data from AD animal models have shown that depletion or inhibition of PERK may exhibit substantial neuroprotection and reduce the amount of AD-related plaques in the AD brains. However, the existing PERK inhibitors are ATP-analogues and represent high toxicity and low specificity in vivo. Our data support the hypothesis that misfolded proteins can directly interact with PERK to activate the PERK signaling pathway. We propose to identify novel inhibitors of PERK that can block the interactions between PERK luminal domain and the misfolded protein by high throughput screening. These small molecular inhibitors may represent novel treatments for AD by attenuating the ER stress signals. We have determined the complex crystal structure of PERK luminal domain and its peptide substrate, which allows us to optimize the identified inhibitors by use of structure-based drug design.