Amyloid fibril formation of alpha-synuclein is accelerated by preformed amyloid seeds of other proteins: implications for the mechanism of transmissible conformational diseases.
Alpha-synuclein is one of the causative proteins of familial Parkinson disease, which is characterized by neuronal inclusions named Lewy bodies. Lewy bodies include not only alpha-synuclein but also aggregates of other proteins. This fact raises a question as to whether the formation of alpha-synuclein amyloid fibrils in Lewy bodies may occur via interaction with fibrils derived from different proteins. To probe this hypothesis, we investigated in vitro fibril formation of human alpha-synuclein in the presence of preformed fibril seeds of various different proteins. We used three proteins, Escherichia coli chaperonin GroES, hen lysozyme, and bovine insulin, all of which have been shown to form amyloid fibrils. Very surprisingly, the formation of alpha-synuclein amyloid fibril was accelerated markedly in the presence of preformed seeds of GroES, lysozyme, and insulin fibrils. The structural characteristics of the natively unfolded state of alpha-synuclein may allow binding to various protein particles, which in turn triggers the formation (extension) of alpha-synuclein amyloid fibrils. This finding is very important for understanding the molecular mechanism of Parkinson disease and also provides interesting implications into the mechanism of transmissible conformational diseases.
Yagi
Hisashi
H
Department of Biotechnology, Faculty of Engineering, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University, Koyama-Minami, Tottori 680-8552, Japan.
Kusaka
Eiko
E
Hongo
Kunihiro
K
Mizobata
Tomohiro
T
Kawata
Yasushi
Y
D000682:Amyloid / Q000737:chemistry*; D000818:Animals; D052160:Benzothiazoles; D001671:Biochemistry / Q000379:methods; D002417:Cattle; D018835:Chaperonin 10 / Q000737:chemistry; D002645:Chickens; D002942:Circular Dichroism; D004926:Escherichia coli / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000737:chemistry / Q000378:metabolism; D016631:Lewy Bodies / Q000378:metabolism; D018625:Microscopy, Atomic Force; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D018832:Molecular Chaperones / Q000737:chemistry; D009113:Muramidase / Q000737:chemistry; D010300:Parkinson Disease / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D012542:Scattering, Radiation; D013844:Thiazoles / Q000737:chemistry; D014965:X-Rays; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism
D000682:Amyloid; D052160:Benzothiazoles; D018835:Chaperonin 10; D007328:Insulin; D018832:Molecular Chaperones; D010455:Peptides; D013844:Thiazoles; D051844:alpha-Synuclein; C009462:thioflavin T; C421864:hen egg lysozyme; D009113:Muramidase