Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.
Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.
Trends Mol Med. 2020 Apr;26(4):408-421. doi: 10.1016/j.molmed.2020.01.005. Epub 2020 Feb 12.
Parkinson's disease (PD) is characterized by progressive loss of dopaminergic neurons and the accumulation of deposits of α-synuclein (α-syn) in the brain. The pivotal role of α-syn aggregation in PD makes it an attractive target for potential disease-modifying therapies. However, the disordered nature of the protein, its multistep aggregation mechanism, and the lack of structural information on intermediate species complicate the discovery of modulators of α-syn amyloid deposition. Despite these difficulties, small molecules have been shown to block the misfolding and aggregation of α-syn, and can even disentangle mature α-syn amyloid fibrils. In this review we provide an updated overview of these leading small compounds and discuss how these chemical chaperones hold great promise to alter the course of PD progression.
帕金森病（PD）的特征是多巴胺能神经元进行性丧失和脑内α-突触核蛋白（α-syn）沉积的积累。α-syn 聚集在 PD 中的关键作用使其成为潜在的疾病修饰治疗的有吸引力的靶标。然而，由于蛋白质的无序性质、其多步骤聚集机制以及中间物种的结构信息缺失，使得发现α-syn 淀粉样蛋白沉积的调节剂变得复杂。尽管存在这些困难，但已经证明小分子可以阻止α-syn 的错误折叠和聚集，甚至可以解开成熟的α-syn 淀粉样纤维。在这篇综述中，我们提供了这些领先的小分子的最新概述，并讨论了这些化学伴侣如何有很大的希望改变 PD 进展的过程。
