title: α-Synuclein structural features inhibit harmful polyunsaturated fatty acid oxidation, suggesting roles in neuroprotection.
abstract: α-Synuclein (aS) is a protein abundant in presynaptic nerve terminals in Parkinson disease (PD) and is a major component of intracellular Lewy bodies, the pathological hallmark of neurodegenerative disorders such as PD. Accordingly, the relationships between aS structure, its interaction with lipids, and its involvement in neurodegeneration have attracted great interest. Previously, we reported on the interaction of aS with brain polyunsaturated fatty acids, in particular docosahexaenoic acid (DHA). aS acquires an α-helical secondary structure in the presence of DHA and, in turn, affects DHA structural and aggregative properties. Moreover, aS forms a covalent adduct with DHA. Here, we provide evidence that His-50 is the main site of this covalent modification. To better understand the role of His-50, we analyzed the effect of DHA on aS-derived species: a naturally occurring variant, H50Q; an oxidized aS in which all methionines are sulfoxides (aS4ox); a fully lysine-alkylated aS (acetyl-aS); and aS fibrils, testing their ability to be chemically modified by DHA. We show, by mass spectrometry and spectroscopic techniques, that H50Q and aS4ox are modified by DHA, whereas acetyl-aS is not. We correlated this modification with aS structural features, and we suggest a possible functional role of aS in sequestering the early peroxidation products of fatty acids, thereby reducing the level of highly reactive lipid species. Finally, we show that fibrillar aS loses almost 80% of its scavenging activity, thus lacking a potentially protective function. Our findings linking aS scavenging activity with brain lipid composition suggest a possible etiological mechanism in some neurodegenerative disorders.
authors.affiliation: From the Department of Pharmaceutical Sciences, CRIBI, Biotechnology Centre, University of Padova, 35121 Padova, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: De Franceschi
authors.affiliation: From the Department of Pharmaceutical Sciences, CRIBI, Biotechnology Centre, University of Padova, 35121 Padova, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Fecchio
authors.affiliation: the Department of Biochemistry and Molecular Biology, IMRIC, The Hebrew University-Hadassah Medical School, 9112102 Jerusalem, Israel.
authors.forename: Ronit
authors.initials: R
authors.lastname: Sharon
authors.affiliation: the Department of Clinical Neuroscience, Institute of Neurology, University College London, NW32PF London, United Kingdom.
authors.forename: Anthony H V
authors.identifier: 0000-0002-3018-3966
authors.initials: AHV
authors.lastname: Schapira
authors.affiliation: the Department of Clinical Neuroscience, Institute of Neurology, University College London, NW32PF London, United Kingdom.
authors.forename: Christos
authors.identifier: 0000-0001-6423-6539
authors.initials: C
authors.lastname: Proukakis
authors.affiliation: the Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, London, United Kingdom, and.|the Department of Molecular Medicine, Institute of Biochemistry, University of Pavia, 27100 Pavia, Italy.
authors.forename: Vittorio
authors.identifier: 0000-0002-0467-864X
authors.initials: V
authors.lastname: Bellotti
authors.affiliation: From the Department of Pharmaceutical Sciences, CRIBI, Biotechnology Centre, University of Padova, 35121 Padova, Italy, patrizia.polverinodelaureto@unipd.it.
authors.forename: Patrizia Polverino
authors.identifier: 0000-0002-0367-6781
authors.initials: PP
authors.lastname: de Laureto
mesh_terms: D016718:Arachidonic Acid / Q000378:metabolism; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D002942:Circular Dichroism; D004281:Docosahexaenoic Acids / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D006801:Humans; D050356:Lipid Metabolism; D008239:Lysine / Q000737:chemistry; D013058:Mass Spectrometry; D008715:Methionine / Q000737:chemistry; D000066829:Neuroprotection; D010100:Oxygen / Q000737:chemistry; D010300:Parkinson Disease / Q000378:metabolism; D017433:Protein Structure, Secondary; D014357:Trypsin / Q000737:chemistry; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D005231:Fatty Acids, Unsaturated; D051844:alpha-Synuclein; D004281:Docosahexaenoic Acids; D016718:Arachidonic Acid; D008715:Methionine; D014357:Trypsin; D008239:Lysine; D010100:Oxygen
keywords: lipid oxidation; mass spectrometry (MS); polyunsaturated fatty acid (PUFA); protein chemical modification; α-synuclein (α-synuclein)