Department of Clinical Biochemistry, University of Kashmir, Srinagar, Jammu and Kashmir 190006, India.
Ageing Res Rev. 2024 Nov;101:102538. doi: 10.1016/j.arr.2024.102538. Epub 2024 Oct 9.
Parkinson's disease (PD) is primarily characterized by loss of dopaminergic neurons in the substantia nigra pars compacta region of the brain and accumulation of aggregated forms of alpha-synuclein (α-Syn), an intrinsically disordered protein, in the form of Lewy Bodies and Lewy Neurites. Substantial evidences point to the aggregated/fibrillar forms of α-Syn as a central event in PD pathogenesis, underscoring the modulation of α-Syn aggregation as a promising strategy for PD treatment. Consequently, numerous anti-aggregation agents, spanning from small molecules to polymers, have been scrutinized for their potential to mitigate α-Syn aggregation and its associated toxicity. Among these, small molecule modulators like osmoprotectants, polyphenols, cellular metabolites, metals, and peptides have emerged as promising candidates with significant potential in PD management. This article offers a comprehensive overview of the effects of these small molecule modulators on the aggregation propensity and associated toxicity of α-Syn and its PD-associated mutants. It serves as a valuable resource for identifying and developing potent, non-invasive, non-toxic, and highly specific small molecule-based therapeutic arsenal for combating PD. Additionally, it raises pertinent questions aimed at guiding future research endeavours in the field of α-Syn aggregation remodelling.
帕金森病（PD）的主要特征是大脑黑质致密部多巴胺能神经元丧失和α-突触核蛋白（α-Syn）聚集形式的路易体和路易神经突的积累，α-Syn 是一种固有无序的蛋白质。大量证据表明，聚集/纤维形式的 α-Syn 是 PD 发病机制中的核心事件，强调了调节 α-Syn 聚集作为 PD 治疗的有前途的策略。因此，已经对大量的抗聚集剂（从小分子到聚合物）进行了研究，以评估它们减轻 α-Syn 聚集及其相关毒性的潜力。在这些小分子调节剂中，渗透压调节剂、多酚、细胞代谢物、金属和肽等小分子调节剂作为有前途的候选物脱颖而出，它们在 PD 管理方面具有显著的潜力。本文全面概述了这些小分子调节剂对 α-Syn 及其 PD 相关突变体的聚集倾向和相关毒性的影响。它为识别和开发针对 PD 的有效、非侵入性、无毒和高度特异的基于小分子的治疗武器提供了有价值的资源。此外，它还提出了相关问题，旨在指导 α-Syn 聚集重塑领域的未来研究工作。
