The protein alpha-synuclein is a major constituent of the Lewy Body aggregates that are a hallmark feature of Parkinson’s disease and has been strongly correlated with the disease. Small a-synuclein aggregates are very toxic and may be an early indicator of the disease. We will develop ligands that can specifically label different forms of alpha-synuclein so that we can study when and where damage begins in the PD brain.
Several genetic studies have correlated aggregation of alpha-synuclein with the onset of PD. Similar to proteins involved in other neurodegenerative diseases including Alzheimer’s, the alpha-synuclein protein can aggregate with other alpha-synuclein molecules to form a number of different structures including small oligomeric and larger fibrillar aggregates. Numerous studies suggest that the oligomeric aggregates are the relevant toxic species in PD. We have isolated antibody based reagents that specifically recognize different aggregated structures including various toxic oligomeric aggregates. In this project we will test whether these conformation specific reagents can be used to test when and where the various different toxic aggregate species occur in the brain. We will radioactively label the different reagents and test whether they can bind their target antigens in brain samples from pre-clinical models of PD.
Relevance to Diagnosis/Treatment of Parkinson’s Disease: Aggregation of alpha-synuclein into small toxic structures is a key early step in the progression of PD. Developing ligands that can detect when and where these toxic structures occur can provide both an early diagnostic test for PD as well as providing the a means to therapeutically target and remove the toxic aggregates.
We will develop ligands that can specifically label different forms of alphasynuclein. We will then test whether these different ligands can recognize their targets in samples of brain tissue taken from pre-clinical models of PD. We will test whether different alpha-synuclein forms are labeled as a function of age.
Different aggregate forms of alpha-synuclein can be identified in vitro and in vivo, including various small soluble oligomeric species which are neurotoxic. We isolated antibody fragments that specifically recognize different aggregated forms of the protein alpha-synuclein and showed that these antibody fragments can recognize various different synuclein aggregates in brain tissue from PD pre-clinical models. We further showed that the antibody fragments can be labeled with a radioactive tracer without loss of activity. The labeled antibody fragments can be used in various in vivo applications such as PET and SPECT imaging to identify when and where in brain tissue toxic alpha-synuclein aggregates first appear. This information can provide valuable tools to diagnose and treat PD and to monitor the effectiveness of different therapeutic strategies.