Study Rationale:
The lysosome is an important compartment in cells that degrades obsolete components, such as the lipid glucosylceramide (GC). The degradation of GC depends on the enzyme glucosylceramidase (GCase) in the lysosome, which is deficient in a subset of Parkinson’s disease patients. This defect results in an accumulation of GC in lysosomes, which increases the risk of neurodegeneration. Restoring GCase activity or reducing GC accumulation in lysosomes is therefore considered a therapeutic strategy for Parkinson’s disease. We recently identified a Parkinson’s disease gene that encodes for a GC transporter, which may be of therapeutic interest to lower GC burden in lysosomes.
Hypothesis:
We hypothesize that this GC transporter removes GC out of the lysosomes, which may be important for proper lysosomal function and neuronal health. Our objectives are a) to firmly establish the lipid specificity and transport direction of the GC transporter, b) define the role of the GC transporter in lysosomes, and c) determine whether the GC transporter and GCase are functionally coupled.
Study Design:
Via established biochemical approaches and transport assays, we will determine the lipid specificity and transport direction of the putative GC transporter. In addition, we will determine whether the transporter influences the lipid composition of the cells via lipidomics analysis. The impact of the transporter on parameters of lysosomal and mitochondrial functionality, and autophagy pathways will also be assessed. Next, we will determine whether modulation of the putative GC transporter influences the GCase activity or GC homeostasis. Finally, we will examine whether overexpression of the GC transporter is able to rescue the loss of GCase function in various cell models.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
Preventing GC accumulation in lysosomes is of therapeutic interest for Parkinson’s disease. The lysosomal GC transport system under investigation may become an interesting drug target to lower lysosomal GC content and toxicity in Parkinson’s disease patients affected by GCase mutations.
Next Steps for Development:
We will further validate the GC transporter as a therapeutic target by exploring its neuroprotective potential in preclinical models of GCase dysfunction. In parallel, our biochemical assays will be used in high-throughput screenings for small molecules that modulate the GC transport activity.
Additional Support:
The Michael J. Fox Foundation would like to acknowledge the generous contribution of the Demoucelle Parkinson Charity and the Stop Parkinson Walk as a lead supporter providing funding for this phase of the project.