Role of prion-like proteins in cell fate and memory

所有细胞都建立了适合其功能的细胞内组织。它们还必须对外部信号做出快速反应，或者在细胞迁移过程中改变它们的结构。最近，一个新的水平的动态细胞组织已经出现，蛋白质聚集成颗粒。聚集支持无膜细胞器的形成，涉及多种功能，包括在不利条件下保护细胞因子（应激颗粒），细胞命运决定因素（p颗粒）的分离，朊病毒的形成和记忆的储存。聚集是由赋予这些组合特定属性的蛋白质结构域驱动的。有些表现为液体，有些表现为凝胶，甚至是固体结构。在大多数情况下，这些结构域参与蛋白质的自模板构象变化，导致颗粒与细胞质的其余部分特异性分离。一个重要的特征是，当聚集成核时，它具有整体效应，允许细胞整合环境和细胞内的信号来做出类似开关的决定。长期以来，蛋白质聚集与蛋白质错误折叠和病理甚至致病结构有关，如克雅氏病（朊病毒）和阿尔茨海默病或帕金森病等神经退行性疾病。然而，我们现在有证据表明，在所有生命领域中，许多生理细胞过程都受聚集控制，这表明聚集是一种非常基本的分子机制。由于目前还没有治愈朊病毒或神经退行性疾病的方法，而且我们生活在一个日益老龄化的社会，我们需要了解蛋白质聚集的分子机制，是什么区分了不同的颗粒，是什么将生理组装转化为病理聚集。我们最近在出芽酵母酿酒酵母中发现了一种新的聚集类型。酵母细胞可以含有朊病毒形式的蛋白质。朊病毒的传染性使它们能够在细胞分裂期间传播到子细胞，并具有克隆稳定性。许多酵母蛋白含有朊病毒样结构域，事实上，即使不是所有生物体，也有大多数含有朊病毒样结构域的蛋白质，包括人类。我们发现其中一些蛋白质可以采用另一种状态，我们称之为助记蛋白。记忆门和朊病毒一样，采用了一种新的形状。以蛋白质wh3为例，这种记忆状态促进了细胞记忆的形成和维持。然而，只有已经学习的细胞才包含记忆符。换句话说，与朊病毒不同的是，助记蛋白受到建立这种状态的细胞的限制。与所有其他聚集机制一样，wh3向助记蛋白形式的转化是由分子伴侣调节的。有趣的是，在细胞老化过程中，wh3也会形成终端包裹体，类似于在许多人类疾病中发现的包裹体。此外，我们最近发现其他新的助记词似乎与wh3一起促进记忆形成。因此，我们发现了一个独特的系统，我们可以比较和识别蛋白质聚集的分子机制。我们将利用这个系统来了解这些新助记符的功能，以及助记符是作为一个网络聚集在一起还是独立工作。由于酵母的复制老化很容易获得，我们将确定是否所有记忆子在老化过程中聚集，并确定这些病理样状态的分子原因。我们建议将我们的研究转化为斑马鱼，以了解脊椎动物中记忆门的生物学。我们的研究利用基因强大的生物体的优势来了解含有朊病毒样结构域的蛋白质的生理和病理。我们的目标是在未来将我们的结果转化为其他生物体，以帮助理解朊病毒和神经退行性疾病背后的生物学。

All cells establish an intracellular organization that fits their functions. They also have to respond quickly to external signals or change their architecture during cell migration for example. Recently, a novel level of dynamic cellular organization has emerged, the aggregation of proteins into granules. Aggregation supports the formation of membrane-less organelles involved in diverse functions including the protection of cellular factors upon unfavourable conditions (stress granules), the segregation of cell fate determinants (P-granules), the formation of prions and the storage of memory. Aggregation is driven by protein domains that confer specific properties to these assemblies. Some behave as liquids, other as gels and even solid structures. In most cases, these domains engage the protein in a self-templating conformational change, resulting in a specific unmixing of the granules from the rest of the cytoplasm. An important feature is that when aggregation is nucleated, it has an en masse effect, allowing cells to integrate environmental and intra-cellular cues to make switch-like decisions.Protein aggregation was long associated with protein misfolding and pathological or even pathogenic structures, such as Creutzfledt-Jakob disease (prion) and neurodegenerative diseases like Alzheimer or Parkinson diseases. However, we now have evidences that a number of physiological cellular processes are controlled by aggregation in all kingdoms of life, suggesting that aggregation is a very fundamental molecular mechanism. Since there are currently no cures for prion or neurodegenerative diseases and since we are in an increasingly ageing society, we need to understand the molecular mechanisms of protein aggregation, what distinguishes the different granules and what transforms physiological assemblies in pathological aggregation. We have recently discovered a new type of aggregation in the budding yeast Saccharomyces cerevisiae. Yeast cells can contain proteins that are in a prion form. The infectious property of prions lends them the ability to disseminate to daughter cells during cell division and to be clonally stable. Many yeast proteins contain prion-like domains and in fact most if not all organisms have prion-like domain containing proteins, including humans. We discovered that some of these proteins could adopt another state that we termed mnemon. Mnemons, like prions, adopt a new shape. In the case of the protein Whi3, this mnemon state promotes the formation and the maintenance of a cellular memory. However, only the cells that have learned contain the mnemon. In other words, unlike a prion, a mnemon is confined by the cell that established this state. As all other aggregation mechanisms, Whi3 conversion to the mnemon form is regulated by molecular chaperones. Interestingly, Whi3 also forms terminal inclusions during cellular ageing that resemble inclusion bodies found in many human pathologies. Additionally, we recently found that other new mnemons seem to work alongside Whi3 to promote memory formation. Thus, we have discovered a unique system in which we can compare and identify the molecular mechanisms of protein aggregation. We will exploit this system to understand the functions of these new mnemons and if mnemons aggregate as a network or work independently. Since replicative ageing in yeast is easily accessed, we will determine if all mnemons aggregate during ageing and identify the molecular causes for these pathological-like states. We propose to translate our research to zebrafish to understand the biology of mnemons in vertebrates.Our research takes the advantage of using a genetically powerful organism to understand the physiology as well as the pathology of prion-like domain containing proteins. We aim to translate our results to other organisms in the future to help understanding the biology behind prion and neurodegenerative diseases.