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Conformational Behavior and Aggregation of α-Synuclein in Organic Solvents: Modeling the Effects of Membranes

2003; American Chemical Society; Volume: 42; Issue: 9 Linguagem: Inglês

10.1021/bi027166s

1943-295X

Larissa A. Munishkina, Cassandra Phelan, Vladimir N. Uversky, Anthony L. Fink,

Alzheimer's disease research and treatments

Intracellular proteinaceous inclusions (Lewy bodies and Lewy neurites) of α-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 α-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 α-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 α-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 β-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 α-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 α-synuclein fibrillation.