Study Rationale: Phosphoinositides (PIPs) are a group of lipids that build cell membranes and play critical roles in mechanisms that control cell’s growth, movement, propagation and death. Recent studies point at a causative role for alterations in levels of PIPs in the mechanisms of Parkinson’s disease (PD). In this project, we will establish a collaboration between basic research in the neurochemistry of PD and a drug discovery center to discover small molecules that activate synaptojanin1, an enzyme involved in maintaining the balance of members belonging to the PIP group.
Hypothesis: We hypothesize that small molecules that can activate the synaptojanin1 phosphatase will reestablish homeostasis of PIPs in neuronal cells, modeling PD.
Study Design: In a collaborative study together with scientists at Blavatnik Center for Drug Discovery, we will use high-throughput screening to identify and develop small molecules to activate the phosphatase activity of synaptojanin1 and enhance synaptojanin1 expression levels. Hit molecules will be tested in a test tube and the most promising hit candidates will be analyzed by methods of medicinal chemistry and tested in cell models of PD.
Impact on Diagnosis/Treatment of Parkinson’s disease: This project will identify and validate a new therapeutic target for the treatment of PD.
Next Steps for Development: The small molecule identified in this study will be analyzed and improved for better chemical performances and for testing in preclinical PD models.