Temperature-dependent structural changes of Parkinson's alpha-synuclein reveal the role of pre-existing oligomers in alpha-synuclein fibrillization.
Amyloid fibrils of α-synuclein are the main constituent of Lewy bodies deposited in substantial nigra of Parkinson's disease brains. α-Synuclein is an intrinsically disordered protein lacking compact secondary and tertiary structures. To enhance the understanding of its structure and function relationship, we utilized temperature treatment to study α-synuclein conformational changes and the subsequent effects. We found that after 1 hr of high temperature pretreatment, >80°C, α-synuclein fibrillization was significantly inhibited. However, the temperature melting coupled with circular dichroism spectra showed that α-synuclein was fully reversible and the NMR studies showed no observable structural changes of α-synuclein after 95°C treatment. By using cross-linking and analytical ultracentrifugation, rare amount of pre-existing α-synuclein oligomers were found to decrease after the high temperature treatment. In addition, a small portion of C-terminal truncation of α-synuclein also occurred. The reduction of pre-existing oligomers of α-synuclein may contribute to less seeding effect that retards the kinetics of amyloid fibrillization. Overall, our results showed that the pre-existing oligomeric species is a key factor contributing to α-synuclein fibrillization. Our results facilitate the understanding of α-synuclein fibrillization.
Genomics Research Center, Academia Sinica, Taipei, Taiwan.
Winny
W
Ariesandi
Chi-Fon
CF
Chang
Tseng-Erh
TE
Chen
Yun-Ru
YR
Chen
D006801:Humans; D010300:Parkinson Disease / Q000378:metabolism*; D011489:Protein Denaturation; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D017384:Sequence Deletion; D013696:Temperature; D051844:alpha-Synuclein / Q000737:chemistry* / Q000235:genetics
D051844:alpha-Synuclein