The protein alpha-synuclein is a major constituent of the Lewy Body aggregates that are a hallmark feature of Parkinson's disease. Several genetic studies have also 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 a small, soluble toxic form. This small toxic oligomeric form has been increasingly implicated as the key toxic species in several neurodegenerative diseases.
We have devised a method to isolate antibody fragments that specifically recognize only these toxic oligomeric structures. In this project we will express these oligomer targeting antibody fragments inside of cells to test whether they can block toxicity of the oligomers and clear them from the cell. A major advantage of targeting only the toxic oligomeric forms of alpha-synuclein, is that all other potentially beneficial forms of the protein are not affected.
The project developed antibodies with higher affinity and specificity for toxic oligomeric alpha-synuclein. Dr. Sierks demonstrated that he could intracellularly target and clear specific alpha-synuclein structures using engineered antibody fragments. Targeting and clearance of different forms of alpha-synuclein provided partial or full protection from toxicity due to intracellular overexpression of alpha-synuclein. These results suggest that targeting and clearing intracellular aggregate forms of alpha-synuclein is a promising therapeutic strategy for treating PD.
Results of this work were published in the journal Neuroscience Letters.