Study Rationale:
Mutations in the GBA1 gene are the highest known risk factor for Parkinson’s disease (PD). In GBA1-associated PD (GBA1/PD), an enzyme in the lysosome of the cell, acid ceramidase, converts glucosylceramide to the highly neurotoxic lipid glucosylsphingosine, and this results in increased a-synuclein aggregation and loss of dopamine neurons, resulting in PD. Inflammation in the brain (neuroinflammation), is a known contributor to PD. Neuroinflammation is predominantly driven by the activation of brain resident immune cells known as microglia. We recently made the observation that in GBA1/PD, acid ceramidase activates microglia, resulting in the formation of aggregated a-synuclein species, and dopamine neuronal death. In this study, we will determine if inhibiting acid ceramidase with a compound that crosses the blood-brain-barrier into the brain and has a good safety profile, can prevent a-synuclein aggregation and neuronal loss.
Hypothesis:
We hypothesize that acid ceramidase is a key therapeutic target for GBA1/PD, and that inhibition of this enzyme will prevent α-synuclein pathology and dopaminergic neuronal loss. We also hypothesize that curbing microglia activation can also help in the treatment of GBA1/PD.
Study Design:
This project is a collaboration between the University of Maryland Baltimore and the University of Alabama at Birmingham (UAB). We will use induced pluripotent stem cells (iPSC) and rodent models of PD to determine if inhibition of acid ceramidase attenuates neuroinflammation, a-synuclein aggregation, and dopamine neuron loss. The Maryland lab will utilize an iPSC model of GBA1/PD consisting of co-cultures of mutant microglia and dopamine neurons, whereas the UAB labs will use a rodent model of GBA1/PD. Working in complementary systems, the 2 teams will determine if inhibition of acid ceramidase with an inhibitor that crosses the blood-brain-barrier, will lower α-synuclein aggregation, reduce the levels of neurotoxic glucosylsphingosine, block neuroinflammation parameters, and increase dopamine neuron survival.
Impact on Diagnosis/Treatment of Parkinson’s disease:
This study will provide a solid foundation for using acid ceramidase inhibition as a disease-modifying therapeutic strategy for GBA1/PD. The proposed work will also provide mechanistic insight on how immune cells of the brain contribute to GBA1/PD.
Next Steps for Development:
This study will provide key safety, pharmacokinetic, and dosing data, which will support future clinical trials of acid ceramidase inhibition for the treatment of GBA1/PD.