title: Structural and morphological characterization of aggregated species of α-synuclein induced by docosahexaenoic acid.
abstract: The interaction of brain lipids with α-synuclein may play an important role in the pathogenesis of Parkinson disease (PD). Docosahexaenoic acid (DHA) is an abundant fatty acid of neuronal membranes, and it is presents at high levels in brain areas with α-synuclein inclusions of patients with PD. In animal models, an increase of DHA content in the brain induces α-synuclein oligomer formation in vivo. However, it is not clear whether these oligomeric species are the precursors of the larger aggregates found in Lewy bodies of post-mortem PD brains. To characterize these species and to define the role of fatty acids in amyloid formation, we investigated the aggregation process of α-synuclein in the presence of DHA. We found that DHA readily promotes α-synuclein aggregation and that the morphology of these aggregates is dependent on the ratio between the protein and DHA. In the presence of a molar ratio protein/DHA of 1:10, amyloid-like fibrils are formed. These fibrils are morphologically different from those formed by α-synuclein alone and have a less packed structure. At a protein/DHA molar ratio of 1:50, we observe the formation of stable oligomers. Moreover, chemical modifications, methionine oxidations, and protein-lipid adduct formations are induced by increasing concentrations of DHA. The extent of these modifications defines the structure and the stability of aggregates. We also show that α-synuclein oligomers are more toxic if generated in the presence of DHA in dopaminergic neuronal cell lines, suggesting that these species might be important in the neurodegenerative process associated with PD.
authors.affiliation: Centro di Ricerca Interdipartimentale per Biotecnologie Innovative (Biotechnology Centre), University of Padova, Viale G. Colombo 3, 35121 Padova, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: De Franceschi
authors.forename: Erica
authors.initials: E
authors.lastname: Frare
authors.forename: Micaela
authors.initials: M
authors.lastname: Pivato
authors.forename: Annalisa
authors.initials: A
authors.lastname: Relini
authors.forename: Amanda
authors.initials: A
authors.lastname: Penco
authors.forename: Elisa
authors.initials: E
authors.lastname: Greggio
authors.forename: Luigi
authors.initials: L
authors.lastname: Bubacco
authors.forename: Angelo
authors.initials: A
authors.lastname: Fontana
authors.forename: Patrizia Polverino
authors.initials: PP
authors.lastname: de Laureto
mesh_terms: D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D055503:Protein Multimerization / Q000187:drug effects*; D017433:Protein Structure, Secondary / Q000187:drug effects; D051844:alpha-Synuclein / Q000737:chemistry* / Q000633:toxicity
chemical_list: D051844:alpha-Synuclein; D004281:Docosahexaenoic Acids; D004298:Dopamine