Drug Discovery and Development Research Group, College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Canada.
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, M5S 3M2, Canada.
J Neurol. 2022 Nov;269(11):5762-5786. doi: 10.1007/s00415-022-11267-9. Epub 2022 Jul 13.
The development of disease-modifying drugs and differential diagnostic agents is an urgent medical need in Parkinson's disease. Despite the complex pathophysiological pathway, the misfolding of alpha-synuclein has been identified as a putative biomarker for detecting the onset and progression of the neurodegeneration associated with Parkinson's disease. Identifying the most appropriate alpha-synuclein-based diagnostic modality with clinical translation will revolutionize the diagnosis of Parkinson's. Likewise, molecules that target alpha-synuclein could alter the disease pathway that leads to Parkinson's and may serve as first-in class therapeutics compared to existing treatment options such as levodopa and dopamine agonist that do not necessarily modify the disease pathway. Notwithstanding the promising benefits that alpha-synuclein presents to therapeutics and diagnostics development for Parkinson's disease, finding ways to address potential challenges such as inadequate preclinical models, safety and efficacy will be paramount to achieving clinical translation. In this comprehensive review paper, we described the role of alpha-synuclein in the pathogenesis of Parkinson's disease, as well as how its structure and function relationship delineate disease onset and progression. We further discussed different alpha-synuclein-based diagnostic modalities including biomolecular assays and molecular imaging. Finally, we presented current small molecules and biologics that are being developed as disease-modifying drugs or positron emission tomography imaging probes for Parkinson's disease.
在帕金森病中，开发疾病修饰药物和鉴别诊断试剂是一项紧迫的医学需求。尽管病理生理学途径很复杂，但已发现α-突触核蛋白的错误折叠是一种潜在的生物标志物，可用于检测与帕金森病相关的神经退行性变的发生和进展。确定最适合帕金森病的基于α-突触核蛋白的诊断方式将彻底改变帕金森病的诊断。同样，靶向α-突触核蛋白的分子可以改变导致帕金森病的疾病途径，并且可能作为一类首创的治疗方法，与现有的治疗选择（如左旋多巴和多巴胺激动剂）相比，后者不一定能改变疾病途径。尽管α-突触核蛋白在帕金森病的治疗和诊断开发方面具有令人鼓舞的益处，但找到解决潜在挑战的方法，如临床前模型不足、安全性和有效性，对于实现临床转化至关重要。在这篇全面的综述文章中，我们描述了α-突触核蛋白在帕金森病发病机制中的作用，以及其结构和功能关系如何描绘疾病的发生和进展。我们进一步讨论了不同的基于α-突触核蛋白的诊断方式，包括生物分子测定和分子成像。最后，我们介绍了目前正在开发的作为疾病修饰药物或正电子发射断层扫描成像探针的小分子和生物制剂，用于帕金森病。
