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A Capped Peptide of the Aggregation Prone NAC 71–82 Amino Acid Stretch of α-Synuclein Folds into Soluble β-Sheet Oligomers at Low and Elevated Peptide Concentrations
Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Linnaeus University, Linnaeus Knowledge Environments, Advanced Materials. (PPL;Linnaeus Ctr Biomat Chem, BMC)
Umeå University, Sweden.
Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. (PPL;Linnaeus Ctr Biomat Chem, BMC)
Uppsala University, Sweden. (Linnaeus Ctr Biomat Chem, BMC;BBCL)ORCID iD: 0000-0002-1253-4283
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2020 (English)In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 21, no 5, p. 1-14, article id 1629Article in journal (Refereed) Published
Abstract [en]

Although Lewy bodies and Lewy neurites are hallmarks of Parkinson's disease (PD) and dementia with Lewy bodies (DLB), misfolded α-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-β-sheet fibrils. A previous characterisation study of fibrils prepared from a capped peptide of the non-amyloid β-component (NAC) 71-82 amino acid stretch of α-synuclein demonstrated an increased aggregation propensity resulting in a cross-β-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 β-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 β-sheet structures that potentially could be used in therapeutic strategies in the fight against progressive neurodegenerative disorders, such as PD and DLB.

Place, publisher, year, edition, pages
Basel, Switzerland: MDPI, 2020. Vol. 21, no 5, p. 1-14, article id 1629
Keywords [en]
capped NAC 71–82 peptide, circular dichroism spectroscopy, molecular dynamics simulations, soluble β-sheet oligomers, Thioflavin T fluorescence, α-synuclein
National Category
Biochemistry and Molecular Biology
Research subject
Chemistry, Biochemistry
Identifiers
URN: urn:nbn:se:lnu:diva-92696DOI: 10.3390/ijms21051629ISI: 000524908500080PubMedID: 32120928Scopus ID: 2-s2.0-85080874648OAI: oai:DiVA.org:lnu-92696DiVA, id: diva2:1412078
Funder
The Dementia Association - The National Association for the Rights of the DementedAvailable from: 2020-03-05 Created: 2020-03-05 Last updated: 2023-01-18Bibliographically approved

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Näsström, ThomasAndersson, Per-OlaKarlsson, Björn C. G.

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