Unraveling client selectivity and pattern recognition of DNAJ molecular chaperones inhibiting intracellular polyglutamine aggregation in neurodegenerative models

揭示 DNAJ 分子伴侣抑制神经退行性模型细胞内多聚谷氨酰胺聚集的客户选择性和模式识别

• 批准号: 446508933
• 负责人: Dr. Gaetano Calabrese
• 金额: --
• 依托单位: Centre for High-Throughput Biology
• 依托单位国家: 德国
• 项目类别: WBP Fellowship
• 财政年份: 2020
• 资助国家: 德国
• 起止时间: 2019-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/446508933?language=en
• 关键词: Unraveling; client; selectivity; pattern; recognition

Many neurodegenerative disorders are characterized by the accumulation of proteins forming toxic aggregates inside neurons. Certain proteins contain regions with a long series of repeated of the same glutamine amino acid, otherwise known as polyglutamine regions (polyQ), that favor the aggregation process. In the cell, the molecular chaperone system maintains a fully operational protein environment by helping proteins reach and retain their final structure, prerequisite for their functionality. Interestingly, two molecular chaperones of the DNAJ family (DNAJB6 and DNAJB8) were recently identified to prevent protein aggregation and prolong the lifespan in Parkinson´s and Huntington’s disease mouse models, making them interesting potential therapeutic targets.Our goal is to better understand how these two chaperones have evolved by identifying which proteins inside the cell require them for proper folding. We will use cutting edge mass spectrometry approaches to identify which proteins interact with the two chaperones and require them for folding. Identification of the repertoire of the so called “client” proteins, together with the determination of a specific pattern on the client proteins recognized by the two chaperones could potentially lead to the identification of new target candidates that can either favor or inhibit polyQ aggregation by modulating DNAJB6/8 anti-aggregation activity. This will allow the potential design of new therapeutic approaches for the treatment of amyloid-based neurodegenerative diseases.

许多神经退行性疾病的特征是蛋白质在神经元内积累形成有毒聚集体。某些蛋白质含有一系列重复的相同谷氨酰胺氨基酸区域，也称为聚谷氨酰胺区域（polyQ），有利于聚集过程。在细胞中，分子伴侣系统通过帮助蛋白质达到并保留其最终结构（其功能的先决条件）来维持完全可操作的蛋白质环境。 DNAJB8）最近被发现可以防止帕金森病和亨廷顿病小鼠模型中的蛋白质聚集并延长寿命，这使它们成为有趣的潜在治疗靶点。我们的目标是通过确定细胞内哪些蛋白质需要它们来更好地了解这两种伴侣是如何进化的。我们将使用最先进的质谱方法来识别哪些蛋白质与两个伴侣相互作用，并需要它们来识别所谓的“客户”的全部功能。蛋白质，再加上确定两个伴侣识别的客户蛋白质的特定模式，可能会导致识别新的目标候选者，这些候选者可以通过调节 DNAJB6/8 抗聚集活性来促进或抑制 PolyQ 聚集。用于治疗基于淀粉样蛋白的神经退行性疾病的新治疗方法的潜在设计。