Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.
Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
CNS Neurosci Ther. 2024 Feb;30(2):e14393. doi: 10.1111/cns.14393. Epub 2023 Aug 10.
Synucleinopathies, including Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB), share a distinct pathological feature, that is, a widespread accumulation of α-synuclein (α-syn) in the brain. There is a significant clinical unmet need for disease-modifying treatments for synucleinopathies. Recently, a seaweed-derived mixture of oligosaccharides sodium oligomannate, GV-971, was approved for Phase 2 clinical trials for PD. This study aimed to further evaluate the therapeutic effects of GV-971 on synucleinopathies using cellular and animal models and explore its associated molecular mechanisms.
α-Syn aggregation was assessed, in vitro and ex vivo, by ThT assay. A dopaminergic neuron cell line, Prnp-SNCA mice, and brain slices from PD and DLB patients were used to determine the efficacy of GV-971 in ameliorating α-syn pathology. Measurements of motor functions, including pole, cylinder, and rotarod tests, were conducted on Prnp-SNCA mice 4 weeks after intragastric administration of GV-971 (200 mg day kg ).
GV-971 effectively prevented α-syn aggregation and even disassembled pre-aggregated α-syn fibrils, in vitro and ex vivo. In addition, GV-971 was able to rescue α-syn-induced neuronal damage and reduced release of extracellular vesicles (EVs), likely via modulating Alix expression. In the Prnp-SNCA mouse model, when treated at the age of 5 months, GV-971 significantly decreased α-syn deposition in the cortex, midbrain, and cerebellum regions, along with ameliorating the motor dysfunctions.
Our results indicate that GV-971, when administered at a relatively early stage of the disease process, significantly reduced α-syn accumulation and aggregation in Prnp-SNCA mice. Furthermore, GV-971 corrected α-syn-induced inhibition of EVs release in neurons, contributing to neuronal protection. Future studies are needed to further assess GV-971 as a promising disease-modifying therapy for PD and other synucleinopathies.
包含帕金森病（PD）、多系统萎缩（MSA）和路易体痴呆（DLB）在内的突触核蛋白病具有一个显著的病理学特征，即脑内广泛聚集α-突触核蛋白（α-syn）。目前，对于突触核蛋白病，临床上非常需要能够改变疾病进程的治疗方法。最近，一种从海藻中提取的寡糖混合物——甘露寡糖二酸（GV-971），已被批准进入 PD 的 2 期临床试验。本研究旨在通过细胞和动物模型进一步评估 GV-971 对突触核蛋白病的治疗效果，并探讨其相关的分子机制。
通过 ThT 检测评估 α-syn 的聚集，包括在体外和脑片样本中。使用多巴胺能神经元细胞系、Prnp-SNCA 小鼠和 PD 和 DLB 患者的脑切片，来确定 GV-971 改善 α-syn 病理的疗效。在 Prnp-SNCA 小鼠给予 GV-971（200mg·kg-1·day-1）灌胃 4 周后，进行运动功能测量，包括棒状和圆筒测试以及转棒测试。
GV-971 可有效阻止 α-syn 的聚集，甚至在体外和脑片样本中分解预先聚集的 α-syn 纤维。此外，GV-971 可挽救 α-syn 诱导的神经元损伤，并减少细胞外囊泡（EVs）的释放，可能是通过调节 Alix 的表达。在 Prnp-SNCA 小鼠模型中，当在 5 月龄时开始治疗时，GV-971 可显著减少皮质、中脑和小脑区域的 α-syn 沉积，并改善运动功能障碍。
我们的研究结果表明，GV-971 在疾病进程的早期阶段给药时，可显著减少 Prnp-SNCA 小鼠的 α-syn 积累和聚集。此外，GV-971 纠正了 α-syn 诱导的神经元 EVs 释放抑制，从而起到神经元保护作用。需要进一步的研究来评估 GV-971 作为 PD 和其他突触核蛋白病有前景的疾病修饰治疗方法的潜力。
