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

许多神经退行性疾病的特点是蛋白质在神经元内形成有毒聚集体的积累。某些蛋白质含有一长串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到达并保持其最终结构来维持一个完全可操作的蛋白质环境，这是蛋白质功能的先决条件。有趣的是，DNAJ家族的两个分子伴侣（DNAJB6和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，使它们成为有趣的潜在治疗靶点。我们的目标是通过识别细胞内哪些蛋白质需要它们进行适当折叠来更好地理解这两种伴侣蛋白是如何进化的。我们将使用尖端的质谱方法来确定哪些蛋白质与两个伴侣相互作用并需要它们进行折叠。鉴定所谓的“客户”蛋白库，以及确定两种伴侣蛋白识别的客户蛋白上的特定模式，可能会导致鉴定新的候选靶标，这些候选靶标可以通过调节DNAJB6/8抗聚集活性来促进或抑制polyQ聚集。这将允许设计治疗淀粉样蛋白为基础的神经退行性疾病的新治疗方法。

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.