What is it about?
Gaucher disease, the inherited deficiency of glucocerebrosidase, is caused by biallelic loss-of-function mutations in the gene GBA1, which is also the most frequent genetic risk factor for Parkinson’s disease. While the development of small-molecule stabilizers of glucocerebrosidase is being considered for both disorders, discovery and optimization of lead compounds is limited by the lack of robust cell-based assays amenable to high-throughput screening format. We developed a comprehensive assay pipeline for preclinical discovery of glucocerebrosidase modulators and began by screening libraries enriched with bioactive compounds with known mechanisms of action. The screen identified small molecules with established relevance to glucocerebrosidase, provided an atlas of potential new molecular targets regulating the GBA1 pathway, and produced a set of promising potential therapeutics.
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Why is it important?
The research team designed a three-step screening funnel to find effective EET drug candidates for Gaucher disease. Their process uses quantitative high-throughput screening (qHTS) in all three steps to rapidly narrow the search for promising treatments.
Perspectives
The three-stage screening approach could be used for conditions beyond Gaucher and Parkinson’s diseases. Theoretically, any lysosomal storage disorder caused by a misfolded protein could be targeted using the approaches.
Yu Chen
Read the Original
This page is a summary of: High-throughput screening for small-molecule stabilizers of misfolded glucocerebrosidase in Gaucher disease and Parkinson’s disease, Proceedings of the National Academy of Sciences, October 2024, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2406009121.
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