Study Rationale: The sphingolipid metabolic pathway is large and complex, comprising hundreds of lipids critical to normal cellular and brain function. Variants in multiple genes regulating sphingolipid metabolism, including GBA1, increase the risk of Parkinson’s disease. A recently identified genetic variant in the gene SPTSSB implicates dysfunction in the synthesis of ceramide, which is a key building block of sphingolipids. Faulty ceramide synthesis results in the formation of abnormal compounds called 1-deoxysphingolipids. These cannot be fully processed to more complex sphingolipids that are required for cellular function and are associated with several neurological disorders. We propose measuring 1-deoxysphingolipids in blood to determine if they are elevated in Parkinson’s disease.
Hypothesis: We hypothesize that plasma 1-deoxysphingolipids, biochemical markers of dysfunctional ceramide synthesis, will be elevated in Parkinson’s disease and that this could potentially identify subtypes of Parkinson’s disease.
Study Design: We will measure lipids produced from both normal and abnormal ceramide synthesis pathways in 300 blood samples, including both Parkinson’s patients and healthy controls. The samples will be from blood materials already collected. Sphingolipids will be measured by a method called mass spectrometry. The relationship between 1-deoxysphingolipids levels and other metabolites, genetic markers and symptoms will be evaluated.
Impact on Diagnosis/Treatment of Parkinson’s disease: Elevated 1-deoxysphingolipids would indicate that an abnormality in ceramide synthesis may occur in Parkinson’s disease. This could result in the development of new therapeutics that correct ceramide synthesis and reduce 1-deoxysphingolipids.
Next Steps for Development: Larger studies will be required to confirm the results. It will be important to study whether 1-deoxysphingolipids are also elevated in brain, if they are directly involved in increasing the risk of developing Parkinson’s and, if so, the biological mechanism. Compounds that reduce 1-deoxysphingolipids levels could be developed and tested as potential therapeutics.