Assessing the Role of Glucosylceramide in Alpha-synuclein-induced Toxicity
Target Advancement Program, 2016
Loss-of-function GBA1 mutations in Gaucher disease result in increased risk for Parkinson's disease (PD). Glucocerebrosidase (GCase) normally breaks down a lipid called glucosylceramide (GluCer) that accumulates due to decreased GCase activity. Previous data have indicated that GluCer directly interacts with alpha-synuclein, the main component of Lewy body inclusions; the GluCer-alpha-syn interaction stabilizes alpha-synuclein, causing it to accumulate into aggregates (clumps). Glucosylceramide-reducing agents are expected to destabilize toxic alpha-synuclein aggregates, rendering them amenable to degradation through cellular clearance systems.
GluCer-reducing agents will prevent the accumulation of pathological alpha-synuclein by increasing its degradation rate, therefore providing a therapeutic benefit.
Well-established small molecule GluCer-reducing agents will be utilized in PD midbrain neuronal models. These cells will be derived from induced pluripotent stem cells ("man-made" stem cells that can become other cell types) that have been reprogrammed from fibroblasts from individuals with PD who have genetic mutations in GBA1 or alpha-synuclien; neuronal models have been fully characterized and demonstrate the presence of pathological a-synuclein. Cultures will be treated with GluCer-reducing agents and analyzed for reductions in pathological alpha-synuclein by amyloid-specific staining (cell labeling) and sequential biochemical extractions. In addition, we will determine if alpha-synuclein reduction reverses downstream toxicity, including lysosomal dysfunction and neuron viability, with our established assays.
Impact on Diagnosis/Treatment of Parkinson's disease:
This study will determine the effect of reducing GluCer on alpha-synuclein pathology in neurons that naturally accumulate alpha-synuclein through genetic mutations. If successful, these data would suggest that manipulating the GluCer metabolizing pathway holds promise as a disease-altering therapeutic for PD. GluCer-reducing therapies are currently approved for the treatment of Gaucher disease; therefore, outcomes of this study have potential to rapidly impact Parkinson's disease patients.
Next Steps for Development:
GluCer-reducing small molecules will be tested in vivo for the ability to reduce pathological alpha-synuclein, using pre-clinical models of PD and Gaucher disease that accumulate alpha-synuclein.
Assistant Professor at Northwestern University
Location: Chicago, Illinois, United States