Researchers at the University of Utah tested more than 150,000 compounds in search of candidates that could reduce levels of alpha-synuclein, a protein that forms clumps and kills neurons, leading to neurodegenerative diseases like Parkinson’s disease and dementia with Lewy bodies.
The study authors edited lab-grown human cells by inserting a light-producing protein derived from fireflies. When the gene responsible for alpha-synuclein production—SNCA—was active, the cells would glow, and when SNCA activity diminished, the light would dim. Researchers were able to test a large number of compounds with high-throughput screening and identified A-443654 as the candidate best able to reduce SNCA activity, thus blocking the production of alpha-synuclein.
When alpha-synuclein forms clumps, it also stresses the cell’s built-in system for clearing misshapen proteins. A-443654 appeared to reduce that stress, indicating it may improve the cell’s ability to clear clumps that have already formed in addition to preventing new clumps from forming. Further research will help determine whether A-443654 can be developed into a treatment for Parkinson’s disease and other synucleinopathies.