Dopamine Analogues Inhibit The Molecular Mechanism Of The ¦Á-synuclein Protein Accumulation

Parkinson's disease (PD) is a most common movement disorder. The neurological hallmark of PD is depleted of dopaminergic neurons and deposit of fibrillar Lewy bodies containing primarily α-synuclein (α-Syn). A growing body of evidence strongly supports that formation of α-Syn fibrils and dopamine (DA) metabolism are closely associated with the pathogenesis of the fatal disease. α-Syn readily aggregates into amyloid fibrils both in vivo and in vitro with a secondary structural transformation. To study the mechanism of structural transformation and aggregation, we constructed the C-terminus truncated fragments of α-Syn and focused on the structural transformation of α-Syn and its fragments in trifluoroethanol. Proteins containing the NAC (non-amyloid component) segment undergo a three-state transition: from native random coil to β-sheet and to α-helical structure, while the NAC deficient fragment and γ-synuclein undergo a typical two-state coil-to-αtransition. The β-sheet form is highly hydrophobic and is prone to self-aggregation. The results suggest that the NAC sequence is essential to β-sheet formation and the aggregation originates from the β-sheet intermediate, which may be implicated in the pathogenesis of PD. To study the relation between neurodegeneration and α-Syn fibrilization, we screened some compounds by thioflavin T fluorescence detection as well as atomic force microscopic imaging, and found that DA and some polyphenol analogs inhibit α-Syn fibrillization with a great efficacy in vitro. The oxidation product of polyphenols, can equally suppress the fibrillization process. The inhibition results from spontaneous oxidation products of these polyphenols, rather than from binding of the aromatic rings. So that chemically synthetic small compounds may be applicable to the development of potential probes for monitoring fibrillization processes of α-Syn in vivo and anti-amyloid drugs for clinical treatment for PD.