Oxidative Stress and Cell Cycle Group, Universitat Pompeu Fabra, C/Doctor Aiguader 88, 08003 Barcelona, Spain.
Institute of Bioengineering of Catalonia (IBEC), Baldiri Reixac 10-12, 08028 Barcelona, Spain.
Int J Mol Sci. 2022 Apr 1;23(7):3950. doi: 10.3390/ijms23073950.
Many neurodegenerative disorders display protein aggregation as a hallmark, Huntingtin and TDP-43 aggregates being characteristic of Huntington disease and amyotrophic lateral sclerosis, respectively. However, whether these aggregates cause the diseases, are secondary by-products, or even have protective effects, is a matter of debate. Mutations in both human proteins can modulate the structure, number and type of aggregates, as well as their toxicity. To study the role of protein aggregates in cellular fitness, we have expressed in a highly tractable unicellular model different variants of Huntingtin and TDP-43. They each display specific patterns of aggregation and toxicity, even though in both cases proteins have to be very highly expressed to affect cell fitness. The aggregation properties of Huntingtin, but not of TDP-43, are affected by chaperones such as Hsp104 and the Hsp40 couple Mas5, suggesting that the TDP-43, but not Huntingtin, derivatives have intrinsic aggregation propensity. Importantly, expression of the aggregating form of Huntingtin causes a significant extension of fission yeast lifespan, probably as a consequence of kidnapping chaperones required for maintaining stress responses off. Our study demonstrates that in general these prion-like proteins do not cause toxicity under normal conditions, and in fact they can protect cells through indirect mechanisms which up-regulate cellular defense pathways.
许多神经退行性疾病都表现出蛋白质聚集作为其特征，亨廷顿蛋白和 TDP-43 聚集体分别是亨廷顿病和肌萎缩性侧索硬化症的特征。然而，这些聚集体是否导致疾病、是次要的副产物，甚至具有保护作用，这是一个有争议的问题。人类蛋白中的突变可以调节聚集体的结构、数量和类型，以及它们的毒性。为了研究蛋白质聚集体在细胞适应性中的作用，我们在一种高度可处理的单细胞模型中表达了不同变体的亨廷顿蛋白和 TDP-43。它们各自显示出特定的聚集和毒性模式，尽管在这两种情况下，蛋白质都必须高度表达才能影响细胞适应性。亨廷顿蛋白的聚集特性，而不是 TDP-43 的聚集特性，受到热休克蛋白 104 和 Hsp40 伴侣 Mas5 等伴侣蛋白的影响，这表明 TDP-43，而不是亨廷顿蛋白衍生物，具有内在的聚集倾向。重要的是，聚集形式的亨廷顿蛋白的表达导致裂殖酵母寿命的显著延长，这可能是由于绑架了维持应激反应关闭所需的伴侣蛋白的结果。我们的研究表明，一般来说，这些类朊病毒蛋白在正常条件下不会引起毒性，事实上，它们可以通过上调细胞防御途径的间接机制来保护细胞。
