PERK as a Central Mediator of Neurotoxicity in Tauopathies

 描述(由申请者提供)：神经官能症是一组19种已知的衰弱神经退行性疾病，在美国有近800万人受到影响。目前，肌萎缩侧索硬化症还没有治愈方法，目前的治疗策略只有暂时的和有限的好处。内质网(ER)应激感受器PERK(蛋白激酶R样ERK)已被证实参与肌萎缩侧索硬化症的发生和发展。然而，PERK通路导致神经元功能障碍的机制仍不清楚。长期目标是更好地了解导致(S)神经细胞功能障碍的机制(S)，总体目标是确定tau和PERK协同作用导致神经元功能障碍的机制。中心假说是，tau和perk参与了一个病理循环，在这个过程中，tau的异常积累长期激活了perk，而活跃的perk激活了有助于产生致病tau的酶。这个循环的总体结果是tau致病途径的增强以及蛋白质合成的慢性抑制。表征PERK通路在神经元功能障碍中的作用将确定新的、迫切需要的治疗靶点。这一假设将在三个具体目标上进行检验。AIM 1旨在确定PERK通路在多大程度上导致肌萎缩侧索硬化症的神经元功能障碍。目的2旨在确定PERK活性调节tau病理的机制。最后，目标3将确定PERK通路在一种新描述的被称为初级年龄相关性脊椎病(部分)的脊椎病中的激活程度。在目标1中，我们将使用药理学和遗传学方法在体内、原位和体外模型中抑制PERK；神经功能将通过认知测试、一种名为锰增强MRI的新的非侵入性成像方法和电生理测量来测量。其次，我们将使用生化、免疫组织化学和基因表达分析来确定PERK活性的程度。在目标2中，我们将使用药理学和遗传学方法来激活和抑制体内和体外的tau病模型中的PERK；我们将测量病理Tau和PERK通路的变化。最后，在目标3中，我们将测量部分脑脊液和脑实质中PERK通路标志物和病理tau水平的变化。这将是第一个广泛的部分生化方法，可能会揭示这种疾病的新生物标记物。致病的PERK-tau循环的识别是创新的，因为它通过识别可导致神经元功能障碍(下游)的疾病效应因子(PERK)，同时也增强了tau的异常(上游)，从而偏离了现状。因此，PERK途径提供了一系列独特的新的治疗靶点，可以在多个方面调节疾病。这种方法意义重大，因为该通路在疾病中发挥着核心作用，因此有可能为tauopathy提供治疗解决方案。

 DESCRIPTION (provided by applicant): Tauopathies are a group of nineteen known debilitating neurodegenerative disorders that affect nearly eight million people in the United States. Currently, there is no cure for tauopathies, and there are temporary and limited benefits to current therapeutic strategies. The endoplasmic reticulum (ER) stress sensor PERK (protein kinase R-like ER kinase) has been identified as a participant in the pathogenesis and progression of tauopathies. However, the mechanism by which the PERK pathway causes neuronal dysfunction is still unknown. The long-term goal is to better understand the mechanism(s) that induce(s) neuronal dysfunction in tauopathies, and the overall objective is to determine the mechanism by which tau and PERK synergize to induce neuronal dysfunction. The central hypothesis is that tau and PERK engage in a pathological cycle whereby aberrant accumulation of tau chronically activates PERK, and active PERK activates enzymes that contribute to the production of pathogenic tau. The overall consequence of this cycle is potentiation of tau pathogenic pathways as well as chronic inhibition of protein synthesis. Characterizing the role of the PERK pathway in neuronal dysfunction will identify novel, urgently needed therapeutic targets for tauopathies. The hypothesis will be tested in three specific aims. Aim 1 is designed to determine the extent to which the PERK pathway causes neuronal dysfunction in tauopathies. Aim 2 is designed to determine the mechanism by which PERK activity modulates tau pathology. Finally, Aim 3 will determine the extent of PERK pathway activation in a newly described tauopathy called Primary Age-Related Tauopathy (PART). In Aim 1, we will use pharmacologic and genetic approaches to inhibit PERK in in vivo, in situ, and in vitro models of tauopathy; neuronal function will be measured by cognitive tests, a novel and non-invasive imaging approach called manganese-enhanced MRI, and electrophysiological measurements. Secondly, we will use biochemical, immunohistochemical, and gene expression assays to determine the extent of PERK activity. In Aim 2, we will use pharmacologic and genetic approaches to activate and inhibit PERK in in vivo and in vitro models of tauopathy; we will measure changes to pathological tau and the PERK pathway. Finally, in Aim 3, we will measure changes in the levels of PERK pathway markers and pathological tau in PART CSF and brain parenchyma. This will be the first extensive biochemical approach to PART, which could unveil novel biomarkers of the disease. The identification of a pathogenic PERK-tau cycle is innovative because it departs from the status quo by identifying an effector of disease (PERK) that can cause neuronal dysfunction (downstream) while also potentiating tau aberrancies (upstream). Therefore, the PERK pathway offers a unique repertoire of novel therapeutic targets that can modulate disease in multiple aspects. This approach is significant because of the central role the pathway plays in disease, and therefore, the potential to offer therapeutic solutions to tauopathies.