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Amyloid fibrils prepared using an acetylated and methyl amidated peptide model of the alpha-Synuclein NAC 71-82 amino acid stretch contain an additional cross-beta structure also found in prion proteins
Linnaeus Univ, Neurodegenerat Disorders Unit, SE-39231 Kalmar, Sweden.
Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences. FOI Swedish Def Res Agcy, CBRN Def & Secur, SE-90182 Umea, Sweden.
FOI Swedish Def Res Agcy, CBRN Def & Secur, SE-90182 Umea, Sweden.
Linnaeus Univ, Phys Pharm Lab, Ctr Biomat Chem, SE-39231 Kalmar, Sweden.
2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 15949Article in journal (Refereed) Published
Abstract [en]

The 71-82 fragment of the non-amyloid-beta component (NAC) region of the Parkinson's disease (PD) and dementia with Lewy bodies (DLB) related protein alpha-Synuclein, has been reported to be important during protein misfolding. Although reports have demonstrated the importance of this fragment for the aggregation properties of the full-length protein, its exact role in pre-fibrillar oligomerisation, fibrillar growth and morphology has not yet been fully elucidated. Here, we provide evidence that fibrils prepared from an acetylated and methyl amidated peptide of the NAC 71-82 amino acid stretch of alpha-Synuclein are amyloid and contain, in addition to the cross-beta structure detected in the full-length protein fibrils, a cross-beta structure previously observed in prion proteins. These results shed light on the aggregation propensity of the NAC 71-82 amino acid stretch of the full-length protein but also the roles of the N- and C-terminal domains of alpha-Synuclein in balancing this aggregation propensity. The results also suggest that early aggregated forms of the capped NAC 71-82 peptide generated structures were stabilised by an anti-parallel and twisted beta-sheet motif. Due to its expected toxicity, this beta-sheet motif may be a promising molecular target for the development of therapeutic strategies for PD and DLB.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2019. Vol. 9, article id 15949
National Category
Biochemistry and Molecular Biology
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URN: urn:nbn:se:uu:diva-397800DOI: 10.1038/s41598-019-52206-5ISI: 000493898100057PubMedID: 31685848OAI: oai:DiVA.org:uu-397800DiVA, id: diva2:1373260
Funder
Swedish National Infrastructure for Computing (SNIC), 2016/1-499 2017/1-595The Dementia Association - The National Association for the Rights of the DementedAvailable from: 2019-11-26 Created: 2019-11-26 Last updated: 2019-11-26Bibliographically approved

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