Study Rationale: Mutations in the GBA1 gene are the most common known genetic risk factors for Parkinson’s disease (PD). Individuals who carry these mutations not only have an increased risk of developing the disease but also tend to have an earlier onset and more severe progression. GBA1 is responsible for producing a protein called GCase, which is located within the lysosome, a specific cellular compartment critical for processing and recycling cellular waste. Scientists do not understand how the malfunction of GCase leads to PD.
Hypothesis: While all major cell types in the brain express GCase, it is believed that the damage caused by GBA1 mutations is due predominantly to its effects in neurons and microglia, the resident immune cells. Progress in this field has been hampered by the lack of well-characterized, reproducible stem cell models to test this and other hypotheses of GCase function.
Study Design: Leveraging our robotic platform for culturing multiple cell lines in parallel, we will generate high-quality stem cell models expressing known GBA1 mutations. We will generate the cell types most affected in PD — dopaminergic neurons and microglia — from 24 GBA1 mutant and control cell lines. We will optimize the best assays to investigate how GBA1 mutations impact GCase function. To assess reproducibility, the experiments will be conducted simultaneously at two different locations, using independent materials and researchers. We will share detailed cell generation protocols, comprehensive methods for studying GCase, and resulting datasets with the PD research community.
Impact on Diagnosis/Treatment of Parkinson’s disease: While stem-cell-based models are powerful tools for studying PD, the current lack of standard protocols and methods for using these lines in research has led to significant challenges in reproducing results. Building a resource for the PD scientific community that includes robust protocols to make neurons and microglia and rigorous methods to study GCase in cell models, will significantly accelerate progress by ensuring more consistent and comparable results across laboratories.
Next Steps for Development: Insights into GBA1 mutations have the potential to reveal biological mechanisms and biomarkers related to GCase activity, as well as new targets for therapeutic intervention and drug screening.