title: Mechanistic study of the inhibitory activity of Geum urbanum extract against α-Synuclein fibrillation.
abstract: The presence of Lewy bodies and Lewy neurites is a major pathological hallmark of Parkinson's disease and is hypothesized to be linked to disease development, although this is not yet conclusive. Lewy bodies and Lewy neurites primarily consist of fibrillated α-Synuclein; yet, there is no treatment available targeting stabilization of α-Synuclein in its native state. The aim of the present study was to investigate the inhibitory activity of an ethanolic extract of Geum urbanum against α-Synuclein fibrillation and examine the structural changes of α-Synuclein in the presence of the extract. The anti-fibrillation and anti-aggregation activities of the plant extract were monitored by thioflavin T fibrillation assays and size exclusion chromatography, while structural changes were followed by circular dichroism, Fourier transform infrared spectroscopy, intrinsic fluorescence, small angle X-ray scattering and electron microscopy. Since the extract is a complex mixture, structure-function relationships could not be determined. Under the experimental conditions investigated, Geum urbanum was found to inhibit α-Synuclein fibrillation in a concentration dependent way, and to partly disintegrate preformed α-Synuclein fibrils. Based on the structural changes of α-Synuclein in the presence of extract, we propose that Geum urbanum delays α-Synuclein fibrillation either by reducing the fibrillation ability of one or more of the aggregation prone intermediates or by directing α-Synuclein aggregation towards a non-fibrillar state. However, whether these alterations of the fibrillation pathway lead to less pathogenic species is yet to be determined.
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen Ø, Denmark.
authors.forename: Eva S
authors.initials: ES
authors.lastname: Lobbens
authors.affiliation: Department of Molecular Medicine and Byrd Alzheimer Institute, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd, MDC 07, Tampa, FL 33612, USA.
authors.forename: Leonid
authors.initials: L
authors.lastname: Breydo
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen Ø, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Skamris
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen Ø, Denmark.
authors.forename: Bente
authors.initials: B
authors.lastname: Vestergaard
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen Ø, Denmark.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Jäger
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen Ø, Denmark.
authors.forename: Lene
authors.initials: L
authors.lastname: Jorgensen
authors.affiliation: Department of Molecular Medicine and Byrd Alzheimer Institute, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd, MDC 07, Tampa, FL 33612, USA; Department of Biological Science, Faculty of Science, King Abdulaziz University, PO Box 80203, Jeddah 21589, Saudi Arabia; Laboratory of Structural Dynamics, Stability and Folding of Proteins, Institute of Cytology, Russian Academy of Sciences, Tikhoretsky Ave. 4, St. Petersburg 194064, Russia.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Uversky
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen Ø, Denmark. Electronic address: marco.vandeweert@sund.ku.dk.
authors.forename: Marco
authors.initials: M
authors.lastname: van de Weert
mesh_terms: D000682:Amyloid / Q000037:antagonists & inhibitors / Q000737:chemistry*; D052160:Benzothiazoles; D031986:Geum / Q000737:chemistry*; D006801:Humans; D010936:Plant Extracts / Q000737:chemistry*; D066329:Protein Aggregates; D012996:Solutions; D013050:Spectrometry, Fluorescence; D017550:Spectroscopy, Fourier Transform Infrared; D013844:Thiazoles; D051844:alpha-Synuclein / Q000037:antagonists & inhibitors / Q000737:chemistry*
chemical_list: D000682:Amyloid; D052160:Benzothiazoles; D010936:Plant Extracts; D066329:Protein Aggregates; D012996:Solutions; D013844:Thiazoles; D051844:alpha-Synuclein; C009462:thioflavin T
keywords: Amyloid fibrillation; Inhibition of fibrillation; Natural products; Traditional medicine; α-Synuclein