Study Rationale: Disruption of lysosomal glucosylceramide (GluCer) homeostasis is a key risk factor in Parkinson’s disease. ATP10B, a lysosomal GluCer exporter, has been linked to Parkinson’s through loss-of-function mutations or reduced expression. Enhancing ATP10B activity may offer a novel therapeutic strategy by restoring lysosomal lipid balance.
Hypothesis: We hypothesize that small molecule activators of ATP10B can restore lysosomal GluCer homeostasis, and that an AI-driven drug discovery approach will significantly accelerate the identification of such compounds.
Study Design: We will collaborate with SandboxAQ to apply AI-based methods for optimizing the production of purified, active ATP10B protein. In parallel, we will use a related transporter, ATP13A2, to develop and validate the AI screening platform to ultimately identify ATP10B agonists. The project will conclude with a wet-lab validation screen to confirm activity on ATP10B.
Impact on Diagnosis/Treatment of Parkinson’s disease: If successful, this project could lead to the development of disease-modifying therapies for Parkinson’s by restoring lysosomal GluCer balance in certain subsets of patients, including GBA1 mutation carriers.
Next Steps for Development: Validated ATP10B activators will be advanced into lead optimization and preclinical development with the goal of progressing toward clinical trials.