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

概要

[目的(Purpose)]
Parkinson’s disease is a neurodegenerative disease characterized by the formation of neuronal inclusions of a-synuclein in patient brains. As the disease progresses, toxic a-synuclein aggregates transmit throughout the nervous system. No effective
disease-modifying therapy has been established, and preventing a-synuclein aggregation is thought to be one of the most promising approaches to ameliorate the disease. In this study, we have established a method for screening a-synuclein aggregation inhibitory effect of many drugs in a short period of time by combining the two evaluation methods.


[方法ならびに成績(Methods/Results)]
We performed a two-step screening using the thioflavin T assay and a cell-based assay to identify a-synuclein aggregation inhibitors. The first screening, thioflavin T assay, allowed the identification of 30 molecules, among a total of 1,262 FDA-approved small compounds, which showed inhibitory effects on a-synuclein fibrilization. In the second screening, a cell-based aggregation assay, seven out of these 30 candidates were found to prevent a-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 clegans model, which demonstrated the effect of tannic acid against a-synuclein aggregation.


[総括(Conclusion)]
Our two-step screening system is a powerful method for the identification of a-synuclein aggregation inhibitors, and tannic acid is a promising candidate as a disease-modifying drug for Parkinson’s disease.