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Two-step screening method to identify α-synuclein aggregation inhibitors for Parkinson’s disease

Authors :
Makoto, Hideshima
Yasuyoshi, Kimura
César, Aguirre
Keita, Kakuda
Toshihide, Takeuchi
Chi-Jing, Choong
Junko, Doi
Kei, Nabekura
Keiichi, Yamaguchi
Kichitaro, Nakajima
Kousuke, Baba
Seiichi, Nagano
Yuji, Goto
Yoshitaka, Nagai
Hideki, Mochizuki
Kensuke, Ikenaka
Source :
Scientific Reports, Vol 12, Iss 1, Pp 1-11 (2022), Scientific Reports
Publication Year :
2022
Publisher :
Nature Portfolio, 2022.

Abstract

Parkinson’s disease is a neurodegenerative disease characterized by the formation of neuronal inclusions of α-synuclein in patient brains. As the disease progresses, toxic α-synuclein aggregates transmit throughout the nervous system. No effective disease-modifying therapy has been established, and preventing α-synuclein aggregation is thought to be one of the most promising approaches to ameliorate the disease. In this study, we performed a two-step screening using the thioflavin T assay and a cell-based assay to identify α-synuclein aggregation inhibitors. The first screening, thioflavin T assay, allowed the identification of 30 molecules, among a total of 1262 FDA-approved small compounds, which showed inhibitory effects on α-synuclein fibrilization. In the second screening, a cell-based aggregation assay, seven out of these 30 candidates were found to prevent α-synuclein aggregation without causing substantial toxicity. Of the seven final candidates, tannic acid was the most promising compound. The robustness of our screening method was validated by a primary neuronal cell model and a Caenorhabditis elegans model, which demonstrated the effect of tannic acid against α-synuclein aggregation. In conclusion, our two-step screening system is a powerful method for the identification of α-synuclein aggregation inhibitors, and tannic acid is a promising candidate as a disease-modifying drug for Parkinson’s disease.

Details

Language :
English
ISSN :
20452322
Volume :
12
Issue :
1
Database :
OpenAIRE
Journal :
Scientific Reports
Accession number :
edsair.doi.dedup.....5b909fd755913cf9599106599d465ea0