There are currently no disease-modifying therapies or a-synuclein-reducing agents for the treatment of Parkinson's disease (PD) or related synucleinopathies. Recent data has indicated a mechanistic linkage between Gaucher-causing GBA1 mutations that encode lysosomal glucocerebrosidase and PD. Our previous work demonstrated that GBA1 mutations lead to accumulation of the lipid substrate, glucosylceramide (GluCer), in patient neurons. We further demonstrated that GluCer directly converted a-synuclein into pathogenic, oligomeric forms. While these studies indicated that excess GluCer leads to neurodegeneration in PD, therapeutic strategies centered on GluCer reduction through targeting of lipid-synthesizing enzymes for PD are unexplored. Here we will evaluate the therapeutic potential of glucosylceramide synthase (GCS) inhibition using patient-derived midbrain neurons generated from induced pluripotent stem cells. We will test if small molecule GCS inhibitors influence oligomer levels of a-syn in patient neurons harboring SNCA and GBA1 mutations. To determine if GluCer reduction can reverse down stream cellular pathologies associated with a-syn accumulation, vesicular trafficking and protein maturation will be measured. These studies may provide insight into the role of GluCer in the pathophysiology of PD, and lay the foundation for the development of future therapies centered on reduction of lipid substrates for PD.
|Effective start/end date||11/1/16 → 12/31/17|
- The Michael J Fox Foundation for Parkinson's Research (MJFF 12158)