GV-971 attenuates α-Synuclein aggregation and related pathology
© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd..
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 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.
METHODS: α-Syn aggregation was assessed, in vitro and ex vivo, by ThT assay. A dopaminergic neuron cell line, Prnp-SNCAA53T 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-SNCAA53T mice 4 weeks after intragastric administration of GV-971 (200 mg day-1 kg-1 ).
RESULTS: 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-SNCAA53T 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.
CONCLUSIONS: 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-SNCAA53T 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:30 |
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| Enthalten in: |
CNS neuroscience & therapeutics - 30(2024), 2 vom: 01. Feb., Seite e14393 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Yu, Zhenwei [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 01.03.2024 Date Revised 18.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1111/cns.14393 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM360634060 |
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| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd. | ||
| 520 | |a 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 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 | ||
| 520 | |a METHODS: α-Syn aggregation was assessed, in vitro and ex vivo, by ThT assay. A dopaminergic neuron cell line, Prnp-SNCAA53T 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-SNCAA53T mice 4 weeks after intragastric administration of GV-971 (200 mg day-1 kg-1 ) | ||
| 520 | |a RESULTS: 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-SNCAA53T 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 | ||
| 520 | |a CONCLUSIONS: 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-SNCAA53T 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 | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a GV-971 | |
| 650 | 4 | |a Synucleinopathy | |
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| 650 | 4 | |a α-Synuclein aggregation | |
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| 700 | 1 | |a Yang, Ying |e verfasserin |4 aut | |
| 700 | 1 | |a Chan, Robin Barry |e verfasserin |4 aut | |
| 700 | 1 | |a Shi, Min |e verfasserin |4 aut | |
| 700 | 1 | |a Stewart, Tessandra |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Yang |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Zongran |e verfasserin |4 aut | |
| 700 | 1 | |a Lan, Guoyu |e verfasserin |4 aut | |
| 700 | 1 | |a Sheng, Lifu |e verfasserin |4 aut | |
| 700 | 1 | |a Tian, Chen |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Dishun |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Jing |e verfasserin |4 aut | |
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