PERK as a Central Mediator of Neurotoxicity in Tauopathies

 描述（由申请人提供）：Tau病是一组十九种已知的使人衰弱的神经退行性疾病，影响美国近八百万人。目前，还没有治愈tau蛋白病的方法，并且目前的治疗策略具有暂时和有限的益处。内质网（ER）应激传感器PERK（蛋白激酶R样ER激酶）已被确定为参与tau蛋白病的发病机制和进展。然而，PERK通路引起神经元功能障碍的机制仍然未知。长期目标是更好地理解在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，由此tau的异常积累长期激活PERK，并且活性PERK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tau蛋白病治疗靶点。该假设将在三个具体目标中进行检验。目的1旨在确定PERK通路在tau蛋白病中引起神经元功能障碍的程度。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通路激活的程度，在一个新描述的tau蛋白病称为原发性tau蛋白相关的tau蛋白病（部分）。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tau蛋白病模型中抑制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，我们将使用生物化学，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tau蛋白病的体内和体外模型中激活和抑制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通路标志物和病理性tau蛋白水平的变化。这将是PART的第一个广泛的生物化学方法，可以揭示这种疾病的新生物标志物。致病性PERK-tau循环的鉴定是创新的，因为它通过鉴定可引起神经元功能障碍（下游）同时也增强tau异常（上游）的疾病效应物（PERK）而脱离现状。因此，PERK通路提供了一种独特的新的治疗靶点，可以在多个方面调节疾病。这种方法是重要的，因为该途径在疾病中起着核心作用，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.