Objective/Rationale:
The identification and validation of biomarkers of Parkinson’s disease (PD) is crucial for diagnosing the disease early, monitoring disease progression, designing clinical trials and assessing the effectiveness of therapeutic strategies. Alpha-synuclein is a protein that aggregates into clumps in the cells of PD patients. The primary objectives of this project are to identify and characterize alpha-synuclein and post-translational modifications of alpha-synuclein in the blood (red blood cells and plasma) and to determine which of these species correlate with the development of PD and another disorder characterized by alpha-synuclein clumps: Lewy body dementia (LBD).
Project Description:
Using a combination of mass-spectrometry and proteomics-based approaches, researchers plan to assess the chemical integrity of alpha-synuclein and to identify and map the pattern of alpha-synuclein post-translational modification in plasma and in red blood cells from patients with advanced PD and LBD compared to age-matched controls. In collaboration with Dr. Brit Mollenhauer, they will analyze eight to 10 samples from each individual. In addition, they will generate and use a focused library of alpha-synuclein species consisting of all isoforms and post-translationally modified forms to identify one or a set of antibodies that can be later used to identify, capture and quantify alpha-synculein levels and levels of each modification in biological samples.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The identification of a specific isoform or post-translational modification pattern that correlates with PD or LBD and the identification of antibodies that can detect/capture all forms of alpha-synuclein could provide novel insight into the mechanism of the disease. Such success could also lead to the identification of a novel diagnostic marker and the development of assays (characterization tests) for diagnosing and/or monitoring the progression of PD and related disorders.
Anticipated Outcome:
Investigators expect that the proposed studies will lead to the identification of specific isoforms and post-translationally modified forms of alpha-synuclein, some of which may be disease specific. In addition, the antibody results should pave the way for the development of more accurate assays to quantitatively assess the levels of total alpha-synuclein or specific alpha-synuclein species in complex cellular and biological samples. The knowledge developed here can be translated into novel diagnostic tools for diagnosing and/or monitoring the progression of PD and LBD.