GV-971 attenuates a-Synuclein aggregation and related pathology

Rationale: 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 a-synuclein (a-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.Methods: a-Syn aggregation was assessed, in vitro and ex vivo, by ThT assay. A dopaminergic neuron cell line, Prnp-SNCA(A53T) mice, and brain slices from PD and DLB patients were used to determine the efficacy of GV-971 in ameliorating a-syn pathology. Measurements of motor functions, including pole, cylinder, and rotarod tests, were conducted on Prnp-SNCA(A53T) mice 4 weeks after intragastric administration of GV-971 (200 mg day(-1) kg(-1)).Results: GV-971 effectively prevented a-syn aggregation and even disassembled pre-aggregated a-syn fibrils, in vitro and ex vivo. In addition, GV-971 was able to rescue a-syn-induced neuronal damage and reduced release of extracellular vesicles (EVs), likely via modulating Alix expression. In the Prnp-SNCA(A53T) mouse model, when treated at the age of 5 months, GV-971 significantly decreased a-syn deposition in the cortex, midbrain, and cerebellum regions, along with ameliorating the motor dysfunctions.Conclusions: Our results indicate that GV-971, when administered at a relatively early stage of the disease process, significantly reduced a-syn accumulation and aggregation in Prnp-SNCA(A53T) mice. Furthermore, GV-971 corrected a-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.