title: A natural product inhibits the initiation of α-synuclein aggregation and suppresses its toxicity.
abstract: The self-assembly of α-synuclein is closely associated with Parkinson's disease and related syndromes. We show that squalamine, a natural product with known anticancer and antiviral activity, dramatically affects α-synuclein aggregation in vitro and in vivo. We elucidate the mechanism of action of squalamine by investigating its interaction with lipid vesicles, which are known to stimulate nucleation, and find that this compound displaces α-synuclein from the surfaces of such vesicles, thereby blocking the first steps in its aggregation process. We also show that squalamine almost completely suppresses the toxicity of α-synuclein oligomers in human neuroblastoma cells by inhibiting their interactions with lipid membranes. We further examine the effects of squalamine in a Caenorhabditis elegans strain overexpressing α-synuclein, observing a dramatic reduction of α-synuclein aggregation and an almost complete elimination of muscle paralysis. These findings suggest that squalamine could be a means of therapeutic intervention in Parkinson's disease and related conditions.
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.|University Medical Centre Groningen, European Research Institute for the Biology of Aging, University of Groningen, Groningen 9713 AV, The Netherlands.
authors.forename: Michele
authors.initials: M
authors.lastname: Perni
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
authors.forename: Céline
authors.identifier: 0000-0001-9753-3310
authors.initials: C
authors.lastname: Galvagnion
authors.affiliation: Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Alexander
authors.initials: A
authors.lastname: Maltsev
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
authors.forename: Georg
authors.identifier: 0000-0002-6562-7715
authors.initials: G
authors.lastname: Meisl
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.|University Medical Centre Groningen, European Research Institute for the Biology of Aging, University of Groningen, Groningen 9713 AV, The Netherlands.
authors.forename: Martin B D
authors.initials: MB
authors.lastname: Müller
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
authors.forename: Pavan K
authors.initials: PK
authors.lastname: Challa
authors.affiliation: Department of Applied Mathematics and Theoretical Physics, University of Cambridge, Cambridge CB3 0WA, United Kingdom.
authors.forename: Julius B
authors.initials: JB
authors.lastname: Kirkegaard
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
authors.forename: Patrick
authors.identifier: 0000-0002-1204-5340
authors.initials: P
authors.lastname: Flagmeier
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
authors.forename: Samuel I A
authors.initials: SI
authors.lastname: Cohen
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence 50134, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Cascella
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
authors.forename: Serene W
authors.initials: SW
authors.lastname: Chen
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
authors.forename: Ryan
authors.initials: R
authors.lastname: Limbocker
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
authors.forename: Pietro
authors.initials: P
authors.lastname: Sormanni
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
authors.forename: Gabriella T
authors.initials: GT
authors.lastname: Heller
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
authors.forename: Francesco A
authors.initials: FA
authors.lastname: Aprile
authors.affiliation: Biocomputation and Complex Systems Physics Institute (BIFI)-Joint Unit BIFI-IQFR (CSIC), University of Zaragoza, 50018 Zaragoza, Spain.
authors.forename: Nunilo
authors.initials: N
authors.lastname: Cremades
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence 50134, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Cecchi
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence 50134, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Chiti
authors.affiliation: University Medical Centre Groningen, European Research Institute for the Biology of Aging, University of Groningen, Groningen 9713 AV, The Netherlands.
authors.forename: Ellen A A
authors.initials: EA
authors.lastname: Nollen
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
authors.forename: Tuomas P J
authors.initials: TP
authors.lastname: Knowles
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom; mv245@cam.ac.uk bax@nih.gov maz5@georgetown.edu cmd44@cam.ac.uk.
authors.forename: Michele
authors.initials: M
authors.lastname: Vendruscolo
authors.affiliation: Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892; mv245@cam.ac.uk bax@nih.gov maz5@georgetown.edu cmd44@cam.ac.uk.
authors.forename: Adriaan
authors.initials: A
authors.lastname: Bax
authors.affiliation: MedStar-Georgetown Transplant Institute, Georgetown University School of Medicine, Washington, DC 20010 mv245@cam.ac.uk bax@nih.gov maz5@georgetown.edu cmd44@cam.ac.uk.
authors.forename: Michael
authors.initials: M
authors.lastname: Zasloff
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom; mv245@cam.ac.uk bax@nih.gov maz5@georgetown.edu cmd44@cam.ac.uk.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Dobson
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002777:Cholestanols / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008563:Membrane Lipids / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology; D010291:Paresis / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D010300:Parkinson Disease / Q000378:metabolism; D066329:Protein Aggregates / Q000187:drug effects*; D066263:Protein Aggregation, Pathological / Q000517:prevention & control*; D011485:Protein Binding / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D051844:alpha-Synuclein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D001688:Biological Products; D002777:Cholestanols; D008563:Membrane Lipids; D066329:Protein Aggregates; D051844:alpha-Synuclein; C079655:squalamine
keywords: Parkinson’s disease; amyloid formation; drug development; protein aggregation; toxic oligomers