Modulation of α-synuclein aggregation by dopamine in the presence of MPTP and its metabolite

• Published in: The FEBS journal 2011-05, Vol.278 (10), p.1688-1698
• Main Authors: Jethva, Prashant N, Kardani, Jay R, Roy, Ipsita
• Format: Article
• Language: English
• Subjects: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine - metabolism; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine - pharmacology; adverse effects; alpha-Synuclein - chemistry; alpha-Synuclein - drug effects; amyloid; dopamine; Dopamine - pharmacology; fibrillation; fluorescence; Humans; immunoblotting; metabolites; neurotoxins; Parkinson’s disease; pesticides; Protein Structure, Quaternary; reversed-phase high performance liquid chromatography; scanning electron microscopy; synuclein; thioflavin T
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/j.1742-4658.2011.08093.x

The neurotransmitter dopamine has been shown to inhibit fibrillation of α-synuclein by promoting the formation of nonamyloidogenic oligomers. Fibrillation of α-synuclein is accelerated in the presence of pesticides and the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The aim of this study was to determine whether dopamine continues to have an adverse effect on the fibrillation of α-synuclein in the presence of MPTP and its metabolite 1-methyl-4-phenylpyridinum ion (MPP⁺). We also attempted to answer the ambiguous question of whether conversion of MPTP to MPP⁺ is required for the fibrillation of α-synuclein. For this, α-synuclein was incubated in the presence of MPTP and MPP⁺ along with dopamine. The fibrillation of α-synuclein was monitored by Thioflavin T fluorescence and immunoblotting. The morphology of the aggregates formed was observed using scanning electron microscopy. The concentrations of the neurotoxin and its metabolite were estimated by reverse phase HPLC. We found definitive evidence that the conversion of MPTP to MPP⁺ is not required for aggregation of α-synuclein. MPP⁺ was found to accelerate the rate of α-synuclein aggregation even in the absence of components of mitochondrial complex I. In contrast to the effect of dopamine on the aggregation of α-synuclein alone, in the presence of MPTP or MPP⁺, the aggregates formed are Thioflavin T-positive and amyloidogenic. Thus, the effect of dopamine on the nature of aggregates formed in case of α-synuclein alone and in the presence of MPTP/MPP⁺ is different.