Funded Studies
Objective/Rationale:
The goal of this project is to evaluate the interaction of a panel of conformation dependent, aggregation specific anti-amyloid monoclonal antibodies with alpha-synuclein oligomers and fibrils in vitro and in human PD brain. We hope to identify antibodies that recognize alpha-synuclein aggregates in vitro and in human brain. These antibodies would be candidates for further development of immune therapeutics for Parkinson’s disease.
Project Description:
We have produced a panel of 32 unique monoclonal antibodies that recognize common structural elements in amyloid aggregates, like the alpha-synuclein aggregates that are believed to play an important role in PD pathogenesis. Although these antibodies were originally produced against Abeta amyloid from Alzheimer’s disease, we found that many of them recognize common or generic epitopes (or antibody binding sites) that occur on amyloid aggregates from a number of different amyloids made from different protein sequences. For some of these antibodies, we have already shown that interact with alpha-synuclein aggregates in vitro. In this project, we will test the immunoreactivity of all of the antibodies against alpha-synuclein oligomers and fibrils. We will also test whether any of the antibodies can detect pathological oligomers in human PD brain. Antibodies that react with pathological amyloid aggregates in brain would represent candidates for therapeutic development.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
If we find antibodies that are specific for alpha-synuclein oligomers and synuclein aggregates, we plan to test them in pre-clinical models to see if they are capable of preventing or reversing Parkinson’s pathology. If these antibodies prove effective, they would then be considered as candidates for humanizing the antibodies and subsequent human clinical trials.
Anticipated Outcome:
We anticipate that some of the antibodies will recognize alpha-synuclein oligomers as this was presented in the preliminary data we presented in support of the proposal. Twenty-four new antibodies remain to be tested in vitro. We will further characterize the interaction by western blotting to give an idea of the size of the aggregates. We hope that the antibodies that recognize synuclein aggregates will also specifically identify PD pathology in human brain.
Final Outcome
The goal of this proposal is to identify antibodies that are specific for the pathology of alpha synuclein in Parkinson’s disease. These antibodies recognize unique structures in alpha synuclein that is aggregated and these structures are absent in normal synuclein. We identified 9 different monoclonal antibodies that recognize either fibrils or oligomers of alpha synuclein, but not monomers or native alpha synuclein. We stained Parkinson’s and control brain tissue with these antibodies to determine whether they detect pathologically aggregated alpha synuclein in PD. Some of the antibodies demonstrate novel staining patterns, suggesting that different types of aggregate structures are deposited in unique locations in PD. It remains to be established whether and how these unique deposits are associated with PD pathogenesis.