Objective/Rationale:
Alpha-synuclein is involved in the development and progression of Parkinson’s disease unequivocally. Our preliminary data has suggested that there were several alpha-synuclein splicing variants/isoforms in human cerebrospinal fluid (CSF) and plasma. Additionally, the alpha-synuclein splicing variants/isoforms in CSF were different from those in plasma. Thus, the goal of this study is 1) to characterize the alpha-synuclein splicing variants/isoforms in both CSF and plasma, and 2) to test whether they can be used as biomarkers for PD diagnosis as well as its progression, including development of “non-motor” symptoms, e.g. dementia.
Project Description:
Three steps will be taken to accomplish the stated goals. First, various isoforms of alpha-synuclein will be purified from CSF and plasma, followed by the characterization of the proteins with state-of-the-art proteomics. Next, we will ask whether changes in relative abundance of these proteins in CSF correlate with the state and/or stage of PD (by comparing the CSF samples of PD at different stages with age matched controls and patients with other neurodegenerative diseases). Finally, a similar study will be carried out in human plasma. Markers demonstrating high sensitivity and specificity in PD diagnosis and progression will be developed into to be more user friendly for practical use.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The protein/pathogenesis specific markers (alpha-synuclein splicing variants/isoforms), if identified, likely facilitate the process of developing novel neuroprotective/disease-modifying treatments for PD, selection of PD patients for clinical trials, or evaluating the effects of pharmaceutical therapies. A detailed characterization of alpha-synuclein splicing variants/isoforms may also shed more light on the pathogenesis of PD development/progression.
Anticipated Outcome:
The project, if successful, will provide disease specific markers with high sensitivity and specificity in diagnosing PD and monitoring PD progression in user-friendly clinical settings. The uniqueness of this project includes: 1) it investigates a protein (alpha-synuclein) critically linked to PD pathogenesis as biomarkers for the disease, and 2) it emphasizes the transition of CSF candidate biomarkers to plasma that can be readily evaluated even in developing countries or in remote areas of developed countries.