Study Rationale:
Lysosomes -- tiny bubbles inside the cell responsible for disposing of its waste -- don't work as they should in brain cells of people with Parkinson's disease (PD). Lysosomes are filled with various substances, one of which is ceramide. Ceramide metabolism --production and breakdown -- in lysosomes is controlled by four genes (GBA, GALC, SMPD1 and ASAH1), changes (mutations) in which increase the risk of PD. However, it is unknown whether and how changes in ceramide metabolism cause the dysfunction of lysosomes and contribute to Parkinson's disease.
Hypothesis:
We hypothesize that brain cells carrying mutations in the GBA, GALC, SMPD1 or ASAH1 genes have irregular ceramide metabolism, which affects the composition and function of lysosomes and, in turn, contributes to the Parkinson's disease process.
Study Design:
We will engineer nerve cells with mutations in the GBA, GALC, SMPD1 and ASAH1 genes and evaluate how the presence of these mutations affects the shape, number and function of lysosomes. The latter will be evaluated as the capacity of lysosomes to break down cellular waste. In addition, we will use powerful research tools to analyze changes in lipid and protein content of lysosomes, since such changes could underlie lysosomal dysfunction. Finally, we will determine whether alpha-synuclein -- a sticky protein that forms toxic clumps in the brains of people with PD -- accumulates and clumps in our engineered cells.
Impact on Diagnosis/Treatment of Parkinson's disease:
In this study, we aim to determine whether changes in ceramide metabolism in lysosomes damage brain cells in PD. If this is the case, monitoring of lipids and modulation of ceramide metabolism could become promising strategies for diagnosis and treatment, respectively, of Parkinson's disease.
Next Steps for Development:
If successful, our study will explain how changes in ceramide metabolism contribute to PD, encouraging the development of innovative therapies targeting this process. The cells engineered in our study will be made freely available to researchers worldwide, accelerating research on ceramide metabolism and the development of therapies for PD.