TO REPAIR OR TO DIE: THE CELLULAR RESPONSE TO RIBOSOMOPATHY-CAUSING MUTATIONS

蛋白质是生命所必需的一组不同的分子，由组成单元(氨基酸)组成，按照基因决定的序列组装。基因指导信使RNA的产生，信使RNA随后被称为核糖体的复杂纳米机器用作蛋白质合成的模板。在没有核糖体的情况下，例如，当核糖体的83种成分中的一种缺失时，生命就无法维持。部分核糖体缺乏症，例如当一种成分有缺陷或数量减少时，通常是可以容忍的，尽管它与各种统称为核糖体疾病的疾病有关。这些症状包括大量的症状，每个症状都主要影响特定的组织，如血液、骨骼、大脑等。据推测，这些症状在很大程度上源于细胞无法产生足够的蛋白质。然而，我们发现，在核糖体病的动物模型中，细胞显示出许多细胞应激的标记，这通常是由缺陷蛋白的积累引起的。我们已经提出，移除有缺陷的核糖体的需要压倒了通常破坏其他有缺陷的蛋白质的细胞机制。因此，有缺陷的蛋白质会积累，损害细胞的活动，就像路边垃圾收集的中断影响城市生活一样。在核糖体缺陷的组织中，一些细胞经历了凋亡(一种形式的细胞自杀)，而另一些细胞存活下来，并学会了在慢性压力下生活。我们建议使用我们的动物模型以及患者的细胞来破译检测缺陷核糖体存在并控制细胞死亡和修复之间的决定的分子机制。通过了解细胞对缺陷核糖体反应的分子通路，我们将推断出增强细胞保护反应的方法，特别是在神经元中，神经元是一种对缺陷蛋白质的存在特别敏感的细胞。我们预计，我们的结果将开辟新的治疗途径，以缓解核糖体病和可能的其他蛋白质病的症状。

Proteins, a diverse set of molecules that are essential for life, are made up of building blocks (amino acid), assembled in a sequence dictated by genes. Genes direct the production of messenger RNA which are then used as a template for protein synthesis by sophisticated nanomachines called ribosomes. In the absence of ribosomes, e.g. when one of their 83 constituents is missing, life cannot be sustained. Partial ribosome deficiency, e.g. when one constituent is defective or in reduced amount, can often be tolerated, although it is associated with a variety of diseases collectively known as ribosomopathies. These encompass a large number of syndromes that each affect predominantly specific tissues such as the blood, bones, the brain and more. It has been assumed that these symptoms stem largely from the cells' inability to produce sufficient protein. We found however that, in an animal model of ribosomopathy, cells display many markers of cellular stress that is normally caused by the accumulation of defective proteins. We have suggested that the need to remove defective ribosomes overwhelms the cellular machinery that normally destroys other defective proteins. Thus, defective proteins accumulate, impairing the cell's activity, much like interruptions of curb-side waste collection affect city life. Within a ribosome-deficient tissue, some cells undergo apoptosis (a form of cell suicide), while others survive and learn to live with chronic stress. We are proposing to use our animal model as well as cells from patients to decipher the molecular machinery that detects the presence of defective ribosomes and controls the decision between cell death and repair. By understanding the molecular pathways that cells activate in response to defective ribosomes, we will infer ways to boost their protective response, especially in neurons, a type of cells that are particularly sensitive to the presence of defective proteins. We expect that our results will open up new therapeutic avenues to alleviate the symptoms of ribosomopathies and possibly other proteinopathies.