Study Rationale: Neurons derived from the stem cells of people with Parkinson’s disease (PD) offer an excellent vehicle for identifying potentially disease-modifying therapeutic compounds. We previously undertook a screen of 4000 compounds in human PD neurons and identified multiple molecules targeting an exciting potential drug target involved in lipid and calcium biology and in mitochondria. We have found that our compounds are able to correct a number of perturbations in cell physiology found in PD neurons. Here, we seek to understand the mechanisms by which our compounds are working.
Hypothesis: We hypothesize that we can use dopamine neurons derived from the stem cells of people with PD to understand the mechanisms and pathways by which our candidate drugs rescue disease cell phenotypes, knowledge that will ultimately help us develop better drugs for treating PD.
Study Design: Our work has two aims. First, we will explore the mechanisms by which our new compounds are working to correct deficits in calcium and lipid biology seen in patient-derived PD neurons by acting through a key intermediate to activate new beneficial pathways of gene activation. Second, we will test whether our new molecules are acting to benefit mitochondria, the energy powerhouse within cells. We have previously described many ways in which mitochondria are known to fail in PD neurons; here we will see if our new compounds are able to rescue this dysfunction.
Impact on Diagnosis/Treatment of Parkinson’s disease: If successful, this study should facilitate development of new small molecule drug candidates that can be tested and used as a novel PD treatment in the clinic.
Next Steps for Development: Once we have dissected the mechanism by which the drug target works, the next step will be to test whether our new drugs can function in preclinical PD models to improve PD pathology and alleviate symptoms.