Using C. elegans to understand seeding and spreading of tau aggregation

阿尔茨海默病(AD)是一种常见的破坏性神经退行性疾病，目前还没有有效的治疗方法。阿尔茨海默病的根本原因被认为是名为ABeta和tau的蛋白质聚集在一起，形成称为聚集体的大结构。这些团块一旦形成，就可能扩散到大脑的不同细胞。我们的目标是发现tau是如何形成并在细胞间扩散的，以及我们如何能够防止这种情况发生。首先，我们将找出当细胞老化时通常聚集在一起的其他蛋白质是否会导致tau聚集体的形成，从而导致疾病。接下来，我们将对一种名为线虫的微小蠕虫进行基因操作，使其在不同的细胞中产生tau，这为我们提供了一种更好的方法来研究tau是如何聚集在一起并在细胞之间传播的，因为线虫很容易进行基因修改。然后，我们将改变线虫中不同基因的表达，看看这是否会影响tau聚集和传播的进程。特别是，我们将改变通常随年龄增长形成聚集体的蛋白质的水平，以了解这如何影响tau；我们将研究一种称为未折叠蛋白反应(UPR)的途径，该途径也能够在细胞之间传播，看看这是否影响tau的传播。如果我们找到影响tau聚集体的形成和扩散的方法，这些基因和分子途径可能成为开发治疗AD的新药的有希望的靶点，这是一个非常重要的目标，最终可能改善成千上万AD患者和他们的照顾者的生活。

Alzheimer's disease (AD) is a common and devastating neurodegenerative disorder, and there are currently no effective treatments for it. The underlying cause of AD is believed to be the "clumping" together of proteins called ABeta and tau into large structures called aggregates. These clumps, once formed, may then spread into different cells of the brain. We aim to discover how clumps of tau form and spread between cells, and how we might be able to prevent this from happening. First of all, we will find out whether other proteins that normally clump together when cells get older might cause the formation of tau aggregates that lead to disease. Next, we will genetically manipulate a microscopic worm called Caenorhabditis elegans (C. elegans) to produce tau in different cells, giving us a better way to investigate how tau clumps together and spreads between cells, as C. elegans are easy to genetically modify. We will then change the expression of different genes in C. elegans, to see whether this affects the progress of tau clumping and spreading. In particular, we will change the levels of the proteins that normally form aggregates with age, to see how this affects tau; and we will investigate a pathway called the unfolded protein response (UPR) that is also able to spread between cells, to see if this affects the spreading of tau. If we find ways to influence the formation and spreading of tau aggregates, these genes and the molecular pathways may make promising targets for the development of new drugs against AD, a hugely important goal that could ultimately improve the lives of thousands of AD sufferers and their carers.