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
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES(2020)
Abstract
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.
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Key words
alpha-synuclein,capped NAC 71-82 peptide,soluble beta-sheet oligomers,circular dichroism spectroscopy,molecular dynamics simulations,Thioflavin T fluorescence
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