GV-971 attenuates α-Synuclein aggregation and related pathology

Area of Science:

• Neuroscience
• Pharmacology
• Biochemistry

Background:

• Synucleinopathies, including Parkinson's disease (PD), are characterized by alpha-synuclein (α-syn) accumulation in the brain.
• Current treatments for synucleinopathies lack disease-modifying capabilities, highlighting a significant unmet clinical need.
• Sodium oligomannate (GV-971), a seaweed-derived compound, is being investigated for its therapeutic potential in PD.

Purpose of the Study:

• To evaluate the therapeutic effects of GV-971 on synucleinopathies using cellular and animal models.
• To explore the molecular mechanisms underlying GV-971's efficacy in treating synucleinopathies.
• To assess GV-971's potential as a disease-modifying treatment for PD and related disorders.

Main Methods:

• Assessed α-syn aggregation in vitro and ex vivo using Thioflavin T (ThT) assay.
• Utilized a dopaminergic neuron cell line, Prnp-SNCA^A53T mice, and patient brain slices to test GV-971's efficacy.
• Measured motor functions in Prnp-SNCA^A53T mice after GV-971 administration.

Main Results:

• GV-971 prevented α-syn aggregation and disassembled pre-formed fibrils in vitro and ex vivo.
• GV-971 rescued α-syn-induced neuronal damage and reduced extracellular vesicle (EV) release, potentially via Alix modulation.
• In Prnp-SNCA^A53T mice, GV-971 decreased α-syn deposition and improved motor functions.

Conclusions:

• GV-971 significantly reduced α-syn accumulation and aggregation in a mouse model of synucleinopathy.
• GV-971 protected neurons by correcting α-syn-induced inhibition of EV release.
• GV-971 shows promise as a disease-modifying therapy for Parkinson's disease and other synucleinopathies.