PDF(Pubmed)
Abstract：
Protein misfolding and aggregation are involved in several neurodegenerative disorders, such as α-synuclein (αSyn) implicated in Parkinson\'s disease, where new therapeutic approaches remain essential to combat these devastating diseases. Elucidating the microscopic nucleation mechanisms has opened new opportunities to develop therapeutics against toxic mechanisms and species. Here, we show that naturally occurring molecular chaperones, represented by the anti-amyloid Bri2 BRICHOS domain, can be used to target αSyn-associated nucleation processes and structural species related to neurotoxicity. Our findings revealed that BRICHOS predominantly suppresses the formation of new nucleation units on the fibrils surface (secondary nucleation), decreasing the oligomer generation rate. Further, BRICHOS directly binds to oligomeric αSyn species and effectively diminishes αSyn fibril-related toxicity. Hence, our studies show that molecular chaperones can be utilized as tools to target molecular processes and structural species related to αSyn neurotoxicity and have the potential as protein-based treatments against neurodegenerative disorders.
摘要：
蛋白质错误折叠和聚集与几种神经退行性疾病有关，如与帕金森病有关的α-突触核蛋白(αSyn)，在那里，新的治疗方法对于对抗这些毁灭性疾病仍然至关重要。阐明微观成核机制为开发针对毒性机制和物种的疗法开辟了新的机会。这里,我们证明了天然存在的分子伴侣，以抗淀粉样蛋白Bri2BRICHOS结构域为代表，可用于靶向αSyn相关的成核过程和与神经毒性相关的结构种类。我们的发现表明，BRICHOS主要抑制原纤维表面新成核单元的形成（二次成核），降低低聚物生成速率。Further,BRICHOS直接与寡聚αSyn物种结合，并有效降低αSyn原纤维相关毒性。因此，我们的研究表明,分子伴侣可以用作靶向分子过程和与αSyn神经毒性相关的结构种类的工具,并且具有作为基于蛋白质的治疗神经退行性疾病的潜力.
