Study Rationale: Abnormal clumping of alpha-synuclein appears to be an important cause for the death of dopamine cells in Parkinson disease (PD). Recent studies discovered that small amounts of tiny alpha-synuclein aggregates exist in tissues and body fluids of people with PD, and that these “seeds” can induce the formation of further clumping of alpha-synuclein in a test tube. We have found that this seeding capacity depends on the genetic mutation underlying the disease. In this study, we will investigate the reasons for this variability in alpha-synuclein seeding behavior.
Hypothesis: We hypothesize that differences in the chemical modifications of alpha-synuclein proteins are responsible for the differences in seeding capacity of alpha-synuclein in the cerebrospinal fluid (CSF) of individuals with different genetic forms of PD.
Study Design: We will perform seeding aggregation assays on CSF collected from people with different genetic forms of PD to characterize the seeding potential of their alpha-synuclein proteins. We will then analyze the chemical modifications of these different alpha-synuclein proteins and compare their modification patterns and quantities. Lastly, we will characterize the biophysical properties of the different alpha-synuclein forms we identify.
Impact on Diagnosis/Treatment of Parkinson’s disease: Analysis of the factors that determine the seeding and aggregation properties of the alpha-synuclein protein will help us to understand the reasons for the variability in disease progression and provide a basis for more specific treatments targeted at the different subtypes of PD.
Next Steps for Development: Next steps will be to develop tests for distinguishing the different alpha-synuclein subtypes, as well as subtype-specific treatments for diminishing alpha-synuclein aggregation.