Study Rationale: The ability to accurately detect and quantify alpha-synuclein and its pathology-relevant variants represents a major challenge in Parkinson’s disease (PD). Different studies report marked discrepancies in alpha-synuclein levels in biological fluids. In addition, our previous studies, funded by MJFF, showed that most of the antibody-based tests used in clinical studies do not detect all of the relevant alpha-synuclein species. We have identified and characterized three commercially available alpha-synuclein-specific antibodies that are not thrown off by the most common alpha-synuclein modifications and therefore represent better tools for capturing and quantifying the total amount of alpha-synuclein.
Hypothesis: Using the antibodies that we identified and characterized for their ability to detect forms of alpha-synuclein that include those with the most common protein modifications, we propose to develop and validate a robust method for detecting and quantifying total alpha-synuclein in human biological fluids.
Study Design: In this study, we will first further characterize the three lead antibodies to evaluate their capacity to recognize different aggregated conformations of alpha-synuclein and assess their specificity when exposed to complex biological materials. We will then determine the suitability of lead antibodies for use in an assay and develop a sensitive test using the most suitable antibody pair. Lastly, we will technically characterize and validate our antibody-based immunoassay using plasma and cerebrospinal fluid from a cohort of people with PD and healthy controls.
Impact on Diagnosis/Treatment of Parkinson’s disease: Successful development of this assay will enable development of alpha-synuclein as a useful diagnostic biomarker of disease progression for PD, more accurate assessment of therapies that target alpha-synuclein and discovery of novel biomarkers based on the ratios of specific forms of alpha-synuclein to total alpha-synuclein.