In Parkinson’s, a normal cellular protein called alpha-synuclein begins to fold incorrectly (misfold), and this has a central role in the development of the disease. Our research interest is the effect of a particular class of natural cellular fats called sphingolipids on alpha-synuclein folding. Genetic and cell biological studies done by other researchers have shown that changes in sphingolipid metabolism result in alpha-synuclein misfolding. However, it is not clear how those changes are affecting alpha-synuclein.
Our hypothesis is that specific sphingolipids directly affect alpha-synuclein folding in cells.
In many cells, sphingolipids are degraded and otherwise metabolized, making it difficult to establish the impact of sphingolipids on alpha-synuclein folding. We are studying a simplified system in which sphingolipid can be maintained at more stable levels, allowing us to more clearly analyze their effect on alpha synuclein. We will determine whether alpha-synuclein misfolds in the presence of elevated levels of specific sphingolipids. Since cells contain many different kinds of sphingolipids, we will conduct these experiments with a variety of relevant sphingolipids to get a complete picture of changes that may occur in alpha-synuclein.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
Results in support of our hypothesis would show that one or more sphingolipids contribute to the development of Parkinson’s by directly interacting with alpha-synuclein and changing its fold. In turn, such results would suggest that preventing alpha-synuclein from interacting with specific sphingolipids may offer an effective strategy to prevent or treat Parkinson’s disease.
Next Steps for Development:
Screening of small molecule libraries or potential inhibitors from other sources could be undertaken using the current experimental system in order to identify compounds that would prevent sphingolipids from affecting alpha-synuclein. Furthermore, our results may lead to other strategies relevant to the prevention or treatment of Parkinson’s disease.