The effect of the natural osmolyte trimethylamine-N-oxide (TMAO) on the structural properties and fibril formation of the natively unfolded protein human α-synuclein was studied using several physico-chemical methods. TMAO induced folding of α-synuclein: at moderate concentrations, a partially folded intermediate with enhanced propensity for fibrillation accumulated; at higher concentrations, α-synuclein was tightly folded and underwent self-association to form oligomers. The latter conformation was significantly helical and probably represents the physiologically folded form of the protein.
