Oxford Parkinson's Disease Center (OPDC) and Department of Physiology, Anatomy and Genetics, Oxford University, South Parks Road, Oxford, OX1 3QX, UK.
Institut des Maladies Neurodégénératives, UMR 5293, Univ. de Bordeaux, F-33000, Bordeaux, France.
Nat Commun. 2020 Sep 28;11(1):4885. doi: 10.1038/s41467-020-18689-x.
Parkinson's disease (PD) affects millions of patients worldwide and is characterized by alpha-synuclein aggregation in dopamine neurons. Molecular tweezers have shown high potential as anti-aggregation agents targeting positively charged residues of proteins undergoing amyloidogenic processes. Here we report that the molecular tweezer CLR01 decreased aggregation and toxicity in induced pluripotent stem cell-derived dopaminergic cultures treated with PD brain protein extracts. In microfluidic devices CLR01 reduced alpha-synuclein aggregation in cell somas when axonal terminals were exposed to alpha-synuclein oligomers. We then tested CLR01 in vivo in a humanized alpha-synuclein overexpressing mouse model; mice treated at 12 months of age when motor defects are mild exhibited an improvement in motor defects and a decreased oligomeric alpha-synuclein burden. Finally, CLR01 reduced alpha-synuclein-associated pathology in mice injected with alpha-synuclein aggregates into the striatum or substantia nigra. Taken together, these results highlight CLR01 as a disease-modifying therapy for PD and support further clinical investigation.
帕金森病（PD）影响着全球数以百万计的患者，其特征是多巴胺神经元中α-突触核蛋白的聚集。分子钳作为一种针对发生淀粉样变性过程的蛋白质的正电荷残基的抗聚集剂，显示出很高的潜力。在这里，我们报告说分子钳 CLR01 降低了诱导多能干细胞衍生的多巴胺能培养物中用 PD 脑蛋白提取物处理后的聚集和毒性。在微流控装置中，当轴突末端暴露于α-突触核蛋白寡聚体时，CLR01 减少了细胞体中的α-突触核蛋白聚集。然后，我们在过表达人源α-突触核蛋白的小鼠模型中进行了体内测试；在运动缺陷轻微的 12 个月大时开始治疗的小鼠，运动缺陷得到改善，寡聚体α-突触核蛋白负担减少。最后，CLR01 减少了向纹状体或黑质注射α-突触核蛋白聚集体的小鼠中的α-突触核蛋白相关病理。总之，这些结果突出了 CLR01 作为 PD 的一种疾病修饰治疗方法，并支持进一步的临床研究。
