Smith Heather L, Mallucci Giovanna R
Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
Brain. 2016 Aug;139(Pt 8):2113-21. doi: 10.1093/brain/aww101. Epub 2016 May 11.
Activation of the unfolded protein response is emerging as a common theme in protein-misfolding neurodegenerative diseases, with relevant markers observed in patient tissue and mouse models. Genetic and pharmacological manipulation of the pathway in several mouse models has shown that this is not a passive consequence of the neurodegeneration process. Rather, overactivation of the protein kinase RNA-like ER kinase (PERK, encoded by EIF2AK3) branch of the unfolded protein response directly contributes to disease pathogenesis through the critical reduction in neuronal protein synthesis rates, essential for learning and memory and for neuronal survival. The pharmacological inhibition of this process in these models is strikingly neuroprotective, resulting in the discovery of the first small molecule preventing neurodegeneration and clinical disease in vivo This now represents a potential generic approach for boosting memory and preventing neurodegeneration across the spectrum of these disorders, albeit with some exceptions, independent of disease-specific proteins. Targeting the unfolded protein response, and particularly PERK-branch mediated translational failure is thus an increasingly compelling strategy for new treatments for dementia and neurodegenerative disease.
未折叠蛋白反应的激活正成为蛋白质错误折叠神经退行性疾病的一个共同特征，在患者组织和小鼠模型中观察到了相关标志物。在几种小鼠模型中对该通路进行基因和药理学操作表明，这并非神经退行性变过程的被动结果。相反，未折叠蛋白反应中蛋白激酶RNA样内质网激酶（PERK，由EIF2AK3编码）分支的过度激活通过关键地降低神经元蛋白质合成速率，直接导致疾病发病机制，而神经元蛋白质合成速率对学习、记忆和神经元存活至关重要。在这些模型中对这一过程进行药理学抑制具有显著的神经保护作用，从而发现了首个在体内预防神经退行性变和临床疾病的小分子。现在这代表了一种潜在的通用方法，可用于改善这些疾病谱中的记忆并预防神经退行性变，尽管存在一些例外情况，且与疾病特异性蛋白质无关。因此，针对未折叠蛋白反应，特别是PERK分支介导的翻译失败，是治疗痴呆和神经退行性疾病的一种越来越有吸引力的新策略。
