Study Rationale:
The protein alpha-synuclein plays a major role in Parkinson’s disease (PD). Quantification of alpha-synuclein in biological fluids (e.g., cerebrospinal fluid) could help support clinical diagnosis and monitor progression of the disease. We know that modification of alpha-synuclein occurs through processes such as phosphorylation and truncation. Our study aims to (i) identify these modified versions of alpha-synuclein in cerebrospinal fluid, (ii) build assays (experiments) for their quantification and (iii) validate our findings in different cohorts.
Hypothesis:
We hypothesize that modifications of alpha-synuclein are present and quantifiable in cerebrospinal fluid. We also hypothesize that certain types or species of alpha-synuclein are involved in Parkinson’s disease and that a pattern of alpha-synuclein modifications in cerebrospinal fluid (CSF) will reflect disease progression.
Study Design:
We will use mass spectrometry to identify disease-specific modifications of alpha-synuclein from available CSF samples from PD patients and healthy controls at baseline and 24-month follow-up of the De Novo Parkinson’s study. We will develop quantification methods for three to five identified modifications on regular assay formats and with a new, highly sensitive instrument for single molecule detection because we expect these modified proteins to be present in very low amounts in CSF. With these assays, we will analyze samples from several other available cohorts to validate initial findings.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
Understanding more about the species of alpha-synuclein involved in Parkinson’s disease and validating a measure of those species would allow researchers to monitor progression of alpha-synuclein pathology in Parkinson’s disease. That measure could be used to evaluate the impact of disease-modifying therapies in clinical trials. In addition, more specific therapies targeting the modified alpha-synuclein types involved in PD may increase likelihood of success in stopping progression.
Next Steps for Development:
Clinical trials may be able to use the validated quantification of modified alpha-synuclein as an objective measure. In addition, with our established assays we hope to be able to quantify these alpha-synuclein species in more accessible biological fluids, such as blood.