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征在于在神经元内形成毒性聚集体的蛋白质的积累。某些蛋白质含有具有长系列重复的相同谷氨酰胺氨基酸的区域，也称为多聚谷氨酰胺区域（polyQ），其有利于聚集过程。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）来维持完全运作的蛋白质环境。有趣的是，最近发现了DNAJ家族的两种分子伴侣（DNAJB 6和DNAJB 8），它们可以防止蛋白质聚集并延长帕金森病和亨廷顿病小鼠模型的寿命，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种分子伴侣是如何进化的。我们将使用最先进的质谱方法来确定哪些蛋白质与两个分子伴侣相互作用，并需要它们进行折叠。鉴定所谓的“客户”蛋白的库，以及确定由两种分子伴侣识别的客户蛋白上的特定模式，可能导致鉴定新的靶候选物，其可以通过调节DNAJB 6/8抗聚集活性来促进或抑制polyQ聚集。 这将允许潜在的设计新的治疗方法，用于治疗淀粉样蛋白为基础的神经退行性疾病。

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.