Study Rationale:
Genetic variants in the GBA1 gene are among the most important risk factors for Parkinson’s disease. GBA1 encodes an enzyme that breaks down waste inside lysosomes, the cell’s recycling centers. Harmful variants in GBA1 reduce this activity, contributing to toxic build-up of proteins like alpha-synuclein. However, most patient variants remain unclassified, making it difficult to predict risk or guide treatment. This project builds on our previous success in mapping how GBA1 variants affect enzyme function in human cells, now extending into more disease-relevant models and integrating genetic data from large populations.
Hypothesis:
We believe that combining functional assays, neuronal models, and genetic data will reveal how GBA1 variants contribute to Parkinson’s disease and help identify variants that could be targeted therapeutically.
Study Design:
We will study selected GBA1 variants in human cells to understand how they affect enzyme activity, processing, and delivery to lysosomes. Next, we will introduce a large library of GBA1 variants into stem cell–derived neurons carrying alpha-synuclein, and use a fluorescent probe to measure the activity of each variant in parallel. This will allow us to generate a high-resolution map of how GBA1 variants behave in a Parkinson’s-relevant cell type. We will also analyse large genetic datasets to test whether reduced enzyme activity increases Parkinson’s risk, and whether certain activating variants might be protective.
Impact on Diagnosis/Treatment of Parkinson’s disease:
This work will clarify which GBA1 variants are harmful, benign, or potentially beneficial, improving interpretation of genetic test results and supporting development of therapies that restore lysosomal function in people with Parkinson’s disease.
Next Steps for Development:
The results will be shared openly and used to prioritise variants for further testing in neurons and patient samples. The findings will support clinical trials of GBA1-targeted therapies and help identify individuals who may benefit most.