Study Rationale:
People with GBA-associated Parkinson’s disease (PD) lack enzymes that break down certain fatty molecules (e.g., glucosylceramide), preventing their cells from shedding these waste materials and functioning normally. In laboratory models and human cells, we have shown excess generation of a protein called complement 5a (C5a) and its receptor (C5aR), which drive pro-inflammatory processes and tissue damage in Gaucher disease. Gaucher also happens due to faulty GBA genes. This study will use models of PD and test if drugs that block C5aR reduce or stop brain damage and neurological problems.
Hypothesis:
We believe that excess accumulation of GC glucosylceramide due to mutations in the GBA gene causes C5aR-mediated activation of brain cells that trigger an increased inflammatory response, eventually leading to neurodegeneration and mental defects in PD.
Study Design:
To elucidate the mechanisms by which GBA defects trigger C5aR-mediated brain inflammation in PD, we will inject C5aR-specific blocking reagents in models of PD. We will observe these models for alteration in brain inflammation, neurodegeneration, memory and motor function.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
Targeting the C5aR pathway may be a treatment strategy to reduce or stop brain inflammation and neurodegeneration in PD. In addition, C5aR or their signature inflammatory response might be useful as a potential biomarker for PD.
Next Steps for Development:
We will continue testing C5aR blocking reagents in induced pluripotent stem cells-differentiated dopaminergic neurons and microglia developed from blood cells or skin fibroblast of PD patients and control volunteers. Outcomes of this pre-clinical work could permit to test these compounds as a novel adjunctive therapeutic approach for human PD.