Journal
JOURNAL OF MOLECULAR BIOLOGY
Volume 368, Issue 4, Pages 1132-1144Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2007.02.089
Keywords
Parkinson's Disease; AFM; scFv; alpha-synuclein; phage display
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Funding
- NIA NIH HHS [R01 AG017984-04, R01 AG017984, R01 AG017984-01, AG17984, R01 AG017984-03, R01 AG017984-02] Funding Source: Medline
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Protein misfolding and aggregation are pathological aspects of numerous and 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. (c) 2007 Elsevier Ltd. All rights reserved.
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