Journal of Proteomics ( IF 2.8 ) Pub Date : 2020-06-12 , DOI: 10.1016/j.jprot.2020.103862 Andre Melnik 1 , Valentina Cappelletti 2 , Federico Vaggi 3 , Ilaria Piazza 2 , Marco Tognetti 2 , Carmen Schwarz 1 , Gea Cereghetti 1 , Mennat Allah Ahmed 1 , Martin Soste 1 , Kent Matlack 4 , Natalie de Souza 5 , Attila Csikasz-Nagy 6 , Paola Picotti 2
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Aggregation-prone proteins (APPs) have been implicated in numerous human diseases but the underlying mechanisms are incompletely understood. Here we comparatively analysed cellular responses to different APPs. Our study is based on a systematic proteomic and phosphoproteomic analysis of a set of yeast proteotoxicity models expressing different human disease-related APPs, which accumulate intracellular APP inclusions and exhibit impaired growth. Clustering and functional enrichment analyses of quantitative proteome-level data reveal that the cellular response to APP expression, including the chaperone response, is specific to the APP, and largely differs from the response to a more generalized proteotoxic insult such as heat shock. We further observe an intriguing association between the subcellular location of inclusions and the location of the cellular response, and provide a rich dataset for future mechanistic studies. Our data suggest that care should be taken when designing research models to study intracellular aggregation, since the cellular response depends markedly on the specific APP and the location of inclusions. Further, therapeutic approaches aimed at boosting protein quality control in protein aggregation diseases should be tailored to the subcellular location affected by inclusion formation.
Significance
We have examined the global cellular response, in terms of protein abundance and phosphorylation changes, to the expression of five human neurodegeneration-associated, aggregation-prone proteins (APPs) in a set of isogenic yeast models. Our results show that the cellular response to each APP is unique to that protein, is different from the response to thermal stress, and is associated with processes at the subcellular location of APP inclusion formation. These results further our understanding of how cells, in a model organism, respond to expression of APPs implicated in neurodegenerative diseases like Parkinson's, Alzheimer's, and ALS. They have implications for mechanisms of toxicity as well as of protective responses in the cell. The specificity of the response to each APP means that research models of these diseases should be tailored to the APP in question. The subcellular localization of the response suggest that therapeutic interventions should also be targeted within the cell.
中文翻译：
对与疾病相关的易聚集蛋白的细胞内反应的比较分析。
易聚集蛋白 (APPs) 与许多人类疾病有关，但其潜在机制尚不完全清楚。在这里，我们比较分析了细胞对不同 APP 的反应。我们的研究基于对一组表达不同人类疾病相关 APP 的酵母蛋白毒性模型的系统蛋白质组学和磷酸蛋白质组学分析，这些模型会积累细胞内 APP 内含物并表现出生长受损。定量蛋白质组水平数据的聚类和功能富集分析表明，细胞对 APP 表达的反应，包括伴侣反应，是 APP 特有的，并且与对更普遍的蛋白质毒性损伤（如热休克）的反应有很大不同。我们进一步观察到夹杂物的亚细胞位置与细胞反应位置之间的有趣关联，并为未来的机制研究提供了丰富的数据集。我们的数据表明，在设计研究模型来研究细胞内聚集时应该小心，因为细胞反应明显取决于特定的 APP 和内含物的位置。此外，旨在促进蛋白质聚集疾病中蛋白质质量控制的治疗方法应针对受包涵体形成影响的亚细胞位置进行调整。因为细胞反应明显取决于特定的 APP 和内含物的位置。此外，旨在促进蛋白质聚集疾病中蛋白质质量控制的治疗方法应针对受包涵体形成影响的亚细胞位置进行调整。因为细胞反应明显取决于特定的 APP 和内含物的位置。此外，旨在促进蛋白质聚集疾病中蛋白质质量控制的治疗方法应针对受包涵体形成影响的亚细胞位置进行调整。
意义
我们在一组同基因酵母模型中检查了全球细胞反应，在蛋白质丰度和磷酸化变化方面，对五种人类神经退行性变相关、易聚集蛋白 (APP) 的表达。我们的研究结果表明，对每个 APP 的细胞反应是该蛋白质所特有的，不同于对热应激的反应，并且与 APP 包涵体形成的亚细胞位置的过程有关。这些结果进一步加深了我们对模型生物体中细胞如何响应与帕金森氏症、阿尔茨海默氏症和 ALS 等神经退行性疾病有关的 APP 表达的理解。它们对细胞中的毒性机制和保护性反应有影响。对每种 APP 反应的特异性意味着这些疾病的研究模型应针对所讨论的 APP 进行调整。反应的亚细胞定位表明治疗干预也应该在细胞内靶向。
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