title: Conformational behavior and aggregation of alpha-synuclein in organic solvents: modeling the effects of membranes.
abstract: Intracellular proteinaceous inclusions (Lewy bodies and Lewy neurites) of alpha-synuclein are pathological hallmarks of neurodegenerative diseases such as Parkinson's disease, dementia with Lewy bodies (DLB), and multiple systemic atrophy. The molecular mechanisms underlying the aggregation of alpha-synuclein into such filamentous inclusions remain unknown, although many factors have been implicated, including interactions with lipid membranes. To model the effects of membrane fields on alpha-synuclein, we analyzed the structural and fibrillation properties of this protein in mixtures of water with simple and fluorinated alcohols. All solvents that were studied induced folding of alpha-synuclein, with the common first stage being formation of a partially folded intermediate with an enhanced propensity to fibrillate. Protein fibrillation was completely inhibited due to formation of beta-structure-enriched oligomers with high concentrations of methanol, ethanol, and propanol and moderate concentrations of trifluoroethanol (TFE), or because of the appearance of a highly alpha-helical conformation at high TFE and hexafluoro-2-propanol concentrations. At least to some extent, these conformational effects mimic those observed in the presence of phospholipid vesicles, and can explain some of the observed effects of membranes on alpha-synuclein fibrillation.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Cruz, California 95064, USA.
authors.forename: Larissa A
authors.initials: LA
authors.lastname: Munishkina
authors.forename: Cassandra
authors.initials: C
authors.lastname: Phelan
authors.forename: Vladimir N
authors.initials: VN
authors.lastname: Uversky
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Fink
mesh_terms: D000438:Alcohols / Q000494:pharmacology; D052160:Benzothiazoles; D002942:Circular Dichroism; D000431:Ethanol / Q000494:pharmacology; D005456:Fluorescent Dyes / Q000032:analysis; D006801:Humans; D007700:Kinetics; D008027:Light; D008956:Models, Chemical; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000648:ultrastructure; D010743:Phospholipids / Q000737:chemistry* / Q000494:pharmacology; D020005:Propanols / Q000494:pharmacology; D011487:Protein Conformation / Q000187:drug effects; D011489:Protein Denaturation; D017510:Protein Folding; D017433:Protein Structure, Secondary / Q000187:drug effects; D012542:Scattering, Radiation; D012997:Solvents / Q000494:pharmacology; D017550:Spectroscopy, Fourier Transform Infrared / Q000379:methods; D051843:Synucleins; D013844:Thiazoles / Q000032:analysis; D014270:Trifluoroethanol / Q000494:pharmacology; D051844:alpha-Synuclein; D006845:Hydrocarbons, Fluorinated
chemical_list: D000438:Alcohols; D052160:Benzothiazoles; D000431:Ethanol; D005456:Fluorescent Dyes; D009419:Nerve Tissue Proteins; D010743:Phospholipids; D020005:Propanols; D012997:Solvents; D051843:Synucleins; D013844:Thiazoles; D014270:Trifluoroethanol; D051844:alpha-Synuclein; C497604:SNCA protein, human; C009462:thioflavin T; C001337:hexafluoroisopropanol; D006845:Hydrocarbons, Fluorinated