Cross-seeding of Protein Misfolding as a Disease Mechanism

描述(申请人提供)：蛋白质错误折叠障碍(PMD)包括几种不同的疾病，如阿尔茨海默病(AD)、帕金森病、传染性海绵状脑病(TSE，也称为普恩疾病)和2型糖尿病(T2D)等。这些疾病的中心事件是自然表达的蛋白质的错误折叠形式积累，成为有毒的，并导致组织损伤、器官功能障碍和疾病。尽管与不同的PMD相关的临床症状各不相同，但其机制上的许多相似之处表明，不同的病理可能在分子水平上相互作用，相互增强。这一建议是围绕这样一种假设构建的，即与一种PMD相关的错误折叠蛋白可能通过交叉播种机制启动或加速第二种PMD相关疾病的病原级联反应。我们计划利用实验室开发的各种动物模型和新的体外技术来全面研究这一课题。这些研究将集中在PMD组的3种疾病：AD、T2D和TSES。我们最近描述了错误折叠的普鲁恩(PrPSc)和淀粉样蛋白(A)之间的病理相互作用，这两种蛋白分别与TSE和AD有关。我们的结果显示，当两种错误折叠的蛋白质同时存在于大脑中时，这两种疾病都会显著加速。从这些研究中收集的信息鼓励我们进一步进行这一研究，并将其扩展到评估两种最普遍的经前抑郁症：AD和T2D之间的假定相互作用。这个项目的主要目的是评估错误折叠的蛋白质之间的分子串扰，作为这些疾病的发病机制。实验旨在为这些疾病之间的致病相互作用提供动物模型中的概念验证数据，以及各种体外研究，以调查蛋白质错误折叠的交叉播种是否可以部分解释疾病的相互作用。我们还将研究是否可以通过医学上相关的途径(输血)接触到错误折叠的异源寡聚体来诱发或加速这种疾病。该项目的发现可能为理解AD、T2D和TSE等高度流行和隐匿性疾病的病因学和分子基础提供新的范式，并可能为制定疾病预防和干预策略提供新的途径。

DESCRIPTION (provided by applicant): Protein Misfolding Disorders (PMDs) include several diverse diseases such as Alzheimer's disease (AD), Parkinson's disease, transmissible spongiform encephalopathies (TSEs, also known as prion disorders) and type 2 diabetes (T2D), among many others. The central event in these diseases is the accumulation of a misfolded form of a naturally expressed protein, which becomes toxic and induces tissue damage, organ dysfunction and disease. Despite the diversity of clinical symptoms associated to different PMDs, many similarities in their mechanism suggest that distinct pathologies may cross-talk at the molecular level to enhance each other. This proposal is structured around the hypothesis that misfolded proteins associated to one PMD might initiate or accelerate the pathogenic cascade of a second PMD-related disease through a cross-seeding mechanism. We plan to study this subject in a comprehensive way using various animal models and novel in vitro technologies developed in our lab. The studies will focus on 3 diseases of the PMD group: AD, T2D and TSEs. We have recently described the pathological interaction between misfolded prions (PrPSc) and amyloid-¿ (A¿), the proteins implicated in TSEs and AD, respectively. Our results showed that both diseases were dramatically accelerated when the two misfolded proteins were present simultaneously in the brain. The information gathered from these studies encouraged us to pursue further this line of research, and expand it to assess the putative interaction between the two most prevalent PMDs: AD and T2D. The main goal of this project is to evaluate the molecular cross-talk between misfolded proteins as a pathogenic mechanism implicated in the initiation of these diseases. Experiments are designed to provide proof-of-concept data in animal models for a pathogenic interaction among these diseases and various in vitro studies to investigate if cross- seeding of protein misfolding may explain in part the disease interaction. We will also study whether the disease can be induced or accelerated through a medically relevant route of exposure (blood transfusion) to heterologous misfolded oligomeric aggregates. The findings generated in this project may provide a new paradigm to understand the etiology and molecular basis of highly prevalent and insidious diseases, such as AD, T2D and TSEs and may offer new avenues for developing strategies for disease prevention and intervention.