Study Rationale: In people with Parkinson’s disease (PD), alpha-synuclein proteins aggregate to form structures called Lewy Bodies (LBs). These LBs have recently been found to also contain lipid components. The alpha-synuclein protein binds to lipids and fatty acids, and its accumulation can result in lipid imbalance. Specifically, alpha-synuclein can increase the buildup of unsaturated fatty acids. The use of compounds that moderately regulate fatty acid metabolism (for example, by inhibiting stearoyl-CoA desaturase (SCD), an enzyme that synthesizes unsaturated fatty acids) therefore offers a promising therapeutic strategy for treating PD.
Hypothesis: We hypothesize that defining and correcting fatty acid imbalance will prove to be a promising therapeutic strategy for PD.
Study Design: In this project, we will use genetic and biochemical approaches to re-establish fatty acid balance in neurons derived from people with PD and other preclinical PD models and assess the potential for targeting the lipids biosynthesis pathway for PD treatment. We previously identified that decreasing unsaturated fatty acid production by inhibiting SCD as a candidate strategy for treating PD. Inhibiting SCD is now being evaluated as a therapeutic target in clinical trials.
Impact on Diagnosis/Treatment of Parkinson’s disease: Given the increasing association of genes related to the metabolism of lipid and fatty acids with PD, this project will be important in identifying new targets in fatty acid pathways.
Next Steps for Development: If successful, this study will identify a new therapeutic target for PD and provide a foundation for studies in preclinical PD models with potential to progress to human trials.