Study Rationale: Mutations in the GBA1 gene are one of the most common risk factor for Parkinson’s disease (PD). GBA1 encodes glucocerebrosidase, an enzyme that breaks down a lipid called glucosylceramide. Mutations in GBA1 result in the accumulation of glucosylceramide, which is converted into the neurotoxic lipid glucosylsphingosine by the enzyme acid ceramidase. This lipid imbalance interferes with the recycle of cellular materials and causes harmful alpha-synuclein aggregations, a hallmark of PD. Our laboratory found that pharmacological inhibition of acid ceramidase prevents the build-up of aggregated alpha-synuclein and identified the mechanisms involved. In this project we will use genetic and pharmacological approaches to validate acid ceramidase as a therapeutic target for GBA1-associated PD.
Hypothesis: We hypothesize that in carriers of GBA1 mutations, the persistent generation of glucosylsphingosine is a key pathogenic biomarker to the accumulation of harmful alpha-synuclein aggregates. We also hypothesize that pharmacological inhibition of acid ceramidase can decrease alpha-synuclein aggregation and thus prevent or slow progression of GBA1-associated PD.
Study Design: In this study we will use dopaminergic neurons reprogrammed from patients with GBA1-associated PD, to test the effect of promising new acid ceramidase inhibitors for their ability to prevent the formation of pathogenic forms of alpha-synuclein. We will also validate acid ceramidase as a therapeutic target for GBA1-associated PD by genetic ablation of this enzyme in the patient-derived dopaminergic neurons. We will then examine the effect of acid ceramidase inhibition on key nodes of the GBA1/PD pathogenic pathways we previously identified. Our focus will be the lysosomal machinery involved in alpha-synuclein clearance.
Impact on Diagnosis/Treatment of Parkinson’s disease: In this study we will use PD patient-derived dopaminergic neurons, to identify the most effective acid ceramidase inhibitors capable of restoring the ability of the mutant neurons to clear pathogenic alpha-synuclein species. The information obtained using this relevant system will be critical to design clinical trials for GBA1-associated PD.
Next Steps for Development: Next steps is to partner with pharmaceutical companies to test new treatments for Parkinson’s disease. As the University of Maryland is a major center for clinical trials, there will be a very rapid translation to the clinic.