A novel strategy to control protein misfolding diseases and aging: Molecular mechanisms of transcellular chaperone signalling

在我们老龄化的人口中，越来越多的人面临着累积蛋白质错误折叠的破坏性后果，这是导致阿尔茨海默氏症或帕金森氏病或ALS的标志之一。在多细胞环境中，蛋白质错误折叠疾病使用机制在不同的组织和器官中促进和传播疾病。最近的发现已经证实，在整个有机体的背景下，保护性的细胞机制处于允许跨不同组织传递压力和疾病状况的位置。例如，使用C。作为一个模型系统，我们已经证明了在一个组织中诱导的温和应激会导致多个不同组织中的细胞保护性伴侣反应，称为跨细胞伴侣信号传递(Transcell Chaperone Signling，Cell.2013；153(6)：1366-78)。这会增强抗逆性，延长寿命，并保护不同细胞类型的蛋白质不会发生错误折叠。尽管跨细胞伴侣信号是保守的，但到目前为止，这种组织间信号传递的关键角色和分子机制仍然不清楚。利用遗传筛选和转录组分析，我们已经确定了蛋白平衡网络中在不同组织之间激活保护性压力反应中起指导作用的新组件。在这个项目中，我们将重点关注这些新发现的组件，包括参与免疫反应的分泌肽和属于保守的BTB-ZF家族的转录因子。我们将确定它们是如何在线虫的不同组织中发出信号并激活保护反应的。我们将使用组织特异性染色质图谱(CHIP-SEQ)技术来研究BTB-ZF转录因子如何参与蛋白质稳定的调节，以及在应激、疾病和衰老过程中哪些保护性基因程序被启动。最后，我们将确定新发现的成分如何用于开发针对人类蛋白质错误折叠疾病的新的治疗干预措施。特别是，我们将使用线虫的人类蛋白质错误折叠疾病模型来阐明哪些新的成分具有延迟蛋白质聚集的能力，包括阿尔茨海默病和亨廷顿病。

An increasing number of individuals in our aging population is faced with the devastatingconsequences of cumulative protein misfolding, one of the hallmarks leading to Alzheimer's orParkinson's Disease or ALS. In a multicellular setting, protein misfolding diseases use mechanisms topromote and spread the disease across different tissues and organs. Recent findings haveestablished that within the context of an entire organism, protective cellular mechanisms are at placethat allow to communicate stress and disease conditions across different tissues. For example, usingC. elegans as a model system, we have shown that mild stress induced in one tissue leads to a cytoprotectivechaperone response in multiple different tissues, known as Transcellular ChaperoneSignalling (Cell. 2013; 153(6): 1366-78). This results in increased stress resistance, extends lifespanand protects from protein misfolding in different cell types. Although transcellular chaperone signallingis conserved, the key players and the molecular mechanism of this inter-tissue signalling remainelusive thus far. Using genetic screens and transcriptome analysis, we have identified novelcomponents of the proteostasis network that play an instructive role in the activation of protectivestress responses across and between different tissues.In this project we will focus on these newly identified components, that comprise of secreted peptidesinvolved in the immune response and a transcription factor that belongs to the conserved BTB-ZFfamily. We will determine how they signal and activate protective responses in different tissues of C.elegans. We will investigate how the BTB-ZF transcription factor is involved in the regulation ofproteostasis and which protective gene programmes are initiated during stress, disease and aging,using tissue-specific chromatin profiling (ChIP-Seq) techniques in C. elegans.Finally, we will determine how the newly identified components can be used for the development ofnovel therapeutic interventions against human protein misfolding diseases. In particular we willelucidate which of the novel components have the capacity to delay protein aggregation using C.elegans models of human protein misfolding diseases, including Alzheimer's Disease andHuntington's Disease.