PERK as a Central Mediator of Neurotoxicity in Tauopathies

 描述（由申请人提供）：Tau蛋白病是一组 19 种已知的使人衰弱的神经退行性疾病，影响着美国近 800 万人。目前，tau蛋白病无法治愈，当前的治疗策略只能带来暂时且有限的益处。内质网 (ER) 应激传感器 PERK（蛋白激酶 R 样 ER 激酶）已被确定为 tau 蛋白病发病机制和进展的参与者。然而，PERK通路引起神经元功能障碍的机制仍不清楚。长期目标是更好地了解 tau 蛋白病中诱导神经元功能障碍的机制，总体目标是确定 tau 蛋白和 PERK 协同诱导神经元功能障碍的机制。中心假设是 tau 和 PERK 参与病理循环，tau 的异常积累会长期激活 PERK，而活跃的 PERK 会激活有助于产生致病性 tau 的酶。该循环的总体结果是 tau 致病途径的增强以及蛋白质合成的长期抑制。表征 PERK 通路在神经元功能障碍中的作用将为 tau 蛋白病确定新的、急需的治疗靶点。该假设将在三个具体目标上进行检验。目标 1 旨在确定 PERK 通路导致 tau蛋白病中神经元功能障碍的程度。目标 2 旨在确定 PERK 活性调节 tau 病理学的机制。最后，目标 3 将确定新描述的称为原发性年龄相关 Tau 病 (PART) 的 tau 蛋白病中 PERK 通路激活的程度。在目标 1 中，我们将使用药理学和遗传学方法在 tau 蛋白病的体内、原位和体外模型中抑制 PERK；神经元功能将通过认知测试、一种称为锰增强 MRI 的新型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测定来确定 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在体内和体外tau蛋白病模型中激活和抑制PERK；我们将测量病理性 tau 蛋白和 PERK 通路的变化。最后，在目标 3 中，我们将测量 PART CSF 和脑实质中 PERK 通路标记物和病理性 tau 水平的变化。这将是第一个广泛的 PART 生化方法，可能会揭示该疾病的新生物标志物。致病性 PERK-tau 循环的鉴定具有创新性，因为它通过鉴定一种疾病效应物 (PERK) 来打破现状，这种效应物可能导致神经元功能障碍（下游），同时也会加剧 tau 异常（上游）。因此，PERK 通路提供了一系列独特的新型治疗靶点，可以在多个方面调节疾病。这种方法意义重大，因为该途径在疾病中发挥着核心作用，因此有可能为 tau蛋白病提供治疗解决方案。

 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.