Department of Medicine and Surgery, University of Parma, Via Gramsci 14, 43126 Parma, Italy.
Department of Molecular and Translational Medicine, University of Brescia, Via Europa 11, 25123 Brescia, Italy.
Int J Mol Sci. 2023 Aug 29;24(17):13370. doi: 10.3390/ijms241713370.
A proteostasis network represents a sophisticated cellular system that controls the whole process which leads to properly folded functional proteins. The imbalance of proteostasis determines a quantitative increase in misfolded proteins prone to aggregation and elicits the onset of different diseases. Among these, Parkinson's Disease (PD) is a progressive brain disorder characterized by motor and non-motor signs. In PD pathogenesis, alpha-Synuclein (α-Syn) loses its native structure, triggering a polymerization cascade that leads to the formation of toxic inclusions, the PD hallmark. Because molecular chaperones represent a "cellular arsenal" to counteract protein misfolding and aggregation, the modulation of their expression represents a compelling PD therapeutic strategy. This review will discuss evidence concerning the effects of natural and synthetic small molecules in counteracting α-Syn aggregation process and related toxicity, in different in vitro and in vivo PD models. Firstly, the role of small molecules that modulate the function(s) of chaperones will be highlighted. Then, attention will be paid to small molecules that interfere with different steps of the protein-aggregation process. This overview would stimulate in-depth research on already-known small molecules or the development of new ones, with the aim of developing drugs that are able to modify the progression of the disease.
蛋白质稳态网络代表了一个复杂的细胞系统，它控制着导致正确折叠功能蛋白的整个过程。蛋白质稳态的失衡决定了错误折叠的蛋白质数量增加，容易聚集，并引发不同的疾病。其中，帕金森病（PD）是一种进行性的大脑疾病，其特征是运动和非运动症状。在 PD 的发病机制中，α-突触核蛋白（α-Syn）失去其天然结构，引发聚合级联反应，导致形成有毒的包涵体，这是 PD 的标志。由于分子伴侣是对抗蛋白质错误折叠和聚集的“细胞武器库”，因此调节它们的表达是一种有吸引力的 PD 治疗策略。这篇综述将讨论关于天然和合成小分子在对抗 α-Syn 聚集过程和相关毒性方面的作用的证据，这些小分子在不同的体外和体内 PD 模型中得到了验证。首先，将强调调节伴侣功能的小分子的作用。然后，将关注干扰蛋白质聚集过程不同步骤的小分子。这篇综述将激发对已知小分子的深入研究或开发新的小分子，旨在开发能够改变疾病进展的药物。
