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Monomeric α-synuclein (αS) inhibits amyloidogenesis of human prion protein (hPrP) by forming a stable αS-hPrP hetero-dimer.

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Pages 37-43 | Received 13 Jan 2021, Accepted 24 Mar 2021, Published online: 14 Apr 2021
 

ABSTRACT

Intermolecular interaction between hPrP and αS was investigated using high-speed atomic force microscopy, dynamic light scattering, and nuclear magnetic resonance. We found that hPrP spontaneously gathered and naturally formed oligomers. Upon addition of monomer αS with a disordered conformation, poly-dispersive property of hPrP was lost, and hetero-dimer formation started quite coherently, and further oligomerization was not observed. Solution structure of hPrP-αS dimer was firstly characterized using hetero-nuclear NMR spectroscopy. In this hetero-dimeric complex, C-terminal helical region of hPrP was in the molten-globule like state, while specific sites including hot spot and C-terminal region of αS selectively interacted with hPrP. Thus αS may suppress amyloidogenesis of hPrP by trapping the hPrP intermediate by the formation of a stable hetero-dimer with hPrP.

Abbreviations: hPrP, human prion protein of amino acid residues of 23-231; PrPC, cellular form of prion protein; PrPSc, scrapie form of prion protein, HS-AFM; high speed atomic force microscopy; αS, α-synuclein; DLS, dynamic light scattering

Acknowledgments

This work was supported by grants from the Ministry of Health, Labour, and Welfare of Japan [Research on Measures for Intractable Diseases (Prion Disease and Slow Virus Infections, and Development of Low Molecular Weight Medical Chaperone Therapeutics for Prion Diseases #17ek0109075h)] and the Ministry of Education, Culture, Sports, Science, and Technology of Japan (Grants-in Aid for Scientific Research #19H03476). We also thank M. Kobayashi for providing technical help.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Supplementary material

Supplemental data for this article can be accessed here.