Study Rationale: Decreased function of the lysosomal enzyme GCase is associated with Parkinson’s disease (PD). We discovered that LIMP-2, the protein that transports GCase to the lysosome, also enhances GCase activity. We then designed a peptide, based on LIMP-2, that boosts GCase activity in a test tube and in cells that harbor a mutant form of GCase (E326K) associated with PD. We think that increasing GCase enzymatic activity can help people with PD and that such a peptide could be developed into an effective therapeutic in the future.
Hypothesis: We hypothesize that treating neurons derived from people with PD using an optimized LIMP-2 peptide will enhance GCase activity and lysosomal function and facilitate removal of alpha-synuclein aggregates.
Study Design: We obtained somatic body cells from people with PD who harbor the E326K mutant form of GCase and reprogrammed them to form induced pluripotent stem cells (iPSCs). We will now use these iPSCs to produce dopamine neurons, the cells that degenerate in the PD brain. We will characterize the cells and match this information to the clinical data. Lastly, we will expose these cells to our LIMP-2 peptide and determine whether this treatment improves cellular PD “symptoms,” enhancing lysosomal function and clearance of alpha-synuclein aggregates.
Impact on Diagnosis/Treatment of Parkinson’s disease: If successful, this project will bring us closer to developing our peptide into a PD therapeutic. In addition to testing our peptide on cells with a mutant GCase gene (E326K), we will examine its impact on cells expressing alpha-synuclein pathology to explore its effectiveness in a broader context.
Next Steps for Development: After successful completion of this project, we will be ready to test our peptide in preclinical PD models, where we will further evaluate its toxicity, benefits and possible side effects.