Anti-oligomeric single chain variable domain antibody differentially affects huntingtin and α-synuclein aggregates

Abstract 

Huntington’s and Parkinson’s diseases are both neurodegenerative disorders caused at least in part by misfolding and aggregation of huntingtin (htt) and α-synuclein, respectively. Here we use a single chain antibody fragment (scFv) isolated against oligomeric α-synuclein to probe similarities and differences between the aggregation and toxic mechanisms of htt and α-synuclein. When incubated with htt, the scFv both blocks formation of and promotes dissociation of fibrillar aggregates, but stabilizes formation of cytotoxic oligomeric aggregates. Previous studies with monomeric α-synuclein showed the scFv prevented fibrillar aggregation, but blocked toxicity of oligomeric aggregates. These divergent effects suggest the toxic mechanisms of oligomeric aggregates differ among amyloidogenic protein species.

Abbreviations: scFv, single chain variable domain antibody fragment, AFM, atomic force microscopy, LDH, lactate dehydrogenase, HD, Huntington’s disease, SDS–PAGE, sodium dodecylsulfate–polyacrylamide gel electrophoresis, ThS, Thioflavine S

Keywords: Single chain variable domain antibody fragment, Atomic force microscopy, Oligomer, Huntingtin, α-synuclein, Toxicity