A Capped Peptide Of The Aggregation Prone Nac 71-82 Amino Acid Stretch Of Alpha-Synuclein Folds Into Soluble Beta-Sheet Oligomers At Low And Elevated Peptide Concentrations

Although Lewy bodies and Lewy neurites are hallmarks of Parkinson's disease (PD) and dementia with Lewy bodies (DLB), misfolded alpha-synuclein oligomers are nowadays believed to be key for the development of these diseases. Attempts to target soluble misfolded species of the full-length protein have been limited so far, probably due to the fast aggregation kinetics and burial of aggregation prone segments in final cross-beta-sheet fibrils. A previous characterisation study of fibrils prepared from a capped peptide of the non-amyloid beta-component (NAC) 71-82 amino acid stretch of alpha-synuclein demonstrated an increased aggregation propensity resulting in a cross-beta-structure that is also found in prion proteins. From this, it was suggested that capped NAC 71-82 peptide oligomers would provide interesting motifs with a capacity to regulate disease development. Here, we demonstrated, from a series of circular dichroism spectroscopic measurements and molecular dynamics simulations, the molecular-environment-sensitive behaviour of the capped NAC 71-82 peptide in a solution phase and the formation of beta-sheet oligomeric structures in the supernatant of a fibrillisation mixture. These results highlighted the use of the capped NAC 71-82 peptide as a motif in the preparation of oligomeric beta-sheet structures that potentially could be used in therapeutic strategies in the fight against progressive neurodegenerative disorders, such as PD and DLB.