title: Isolation of a human single chain antibody fragment against oligomeric alpha-synuclein that inhibits aggregation and prevents alpha-synuclein-induced toxicity.
abstract: Protein misfolding and aggregation are pathological aspects of numerous neurodegenerative diseases. Aggregates of alpha-synuclein are major components of the Lewy bodies and Lewy neurites associated with Parkinson's Disease (PD). A natively unfolded protein, alpha-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 alpha-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 alpha-synuclein. The scFv described here binds only to an oligomeric form of alpha-synuclein and inhibits both aggregation and toxicity of alpha-synuclein in vitro. This scFv can have potential therapeutic value in controlling misfolding and aggregation of alpha-synuclein in vivo when expressed intracellularly in dopaminergic neurons as an intrabody.
authors: Department of Chemical and Materials Engineering, Arizona State University, Tempe, AZ 85287-6006, USA.
authors: Sharareh
authors: S
authors: Emadi
authors: Hedieh
authors: H
authors: Barkhordarian
authors: Min S
authors: MS
authors: Wang
authors: Philip
authors: P
authors: Schulz
authors: Michael R
authors: MR
authors: Sierks
mesh_terms: D045744:Cell Line, Tumor; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000302:isolation & purification* / Q000494:pharmacology; D018625:Microscopy, Atomic Force; D019151:Peptide Library; D011485:Protein Binding / Q000187:drug effects; D017510:Protein Folding; D051844:alpha-Synuclein / Q000276:immunology / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D007135:Immunoglobulin Variable Region; D019151:Peptide Library; D051844:alpha-Synuclein