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在神经元内积累形成有毒聚集体的蛋白质。某些蛋白质含有相同谷氨酰胺氨基酸的一长串重复区域，也称为多谷氨酰胺区域(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来维持一个完全运作的蛋白质环境，这是其功能的先决条件。有趣的是，最近在帕金森病S和亨廷顿病小鼠模型中发现了两个DNAJ家族的分子伴侣(DNAJB6和DNAJB8)，可以防止蛋白质聚集并延长寿命，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正确折叠来更好地了解这两个伴侣是如何进化的。我们将使用尖端的质谱学方法来确定哪些蛋白质与这两个伴侣相互作用，并需要它们进行折叠。识别所谓的“客户”蛋白的谱系，以及确定由两个伴侣识别的客户蛋白上的特定模式，可能会导致识别新的候选靶标，这些候选靶标可以通过调节DNAJB6/8的抗聚集活性来促进或抑制多聚Q聚集。这将使设计新的治疗方法成为可能，以治疗基于淀粉样蛋白的神经退行性疾病。