Isolation of a Human Single Chain Antibody Fragment Against Oligomeric α-Synuclein that Inhibits Aggregation and Prevents α-Synuclein-induced Toxicity

Sharareh Emadi, Hedieh Barkhordarian, Min S. Wang, Philip Schulz, Michael Sierks

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Protein misfolding and aggregation are pathological aspects of numerous neurodegenerative diseases. Aggregates of α-synuclein are major components of the Lewy bodies and Lewy neurites associated with Parkinson's Disease (PD). A natively unfolded protein, α-synuclein can adopt different aggregated morphologies, including oligomers, protofibrils and fibrils. The small oligomeric aggregates have been shown to be particularly toxic. Antibodies that neutralize the neurotoxic aggregates without interfering with beneficial functions of monomeric α-synuclein can be useful therapeutics. We were able to isolate single chain antibody fragments (scFvs) from a phage displayed antibody library against the target antigen morphology using a novel biopanning technique that utilizes atomic force microscopy (AFM) to image and immobilize specific morphologies of α-synuclein. The scFv described here binds only to an oligomeric form of α-synuclein and inhibits both aggregation and toxicity of α-synuclein in vitro. This scFv can have potential therapeutic value in controlling misfolding and aggregation of α-synuclein in vivo when expressed intracellularly in dopaminergic neurons as an intrabody.


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