Isolation of short peptide fragments from alpha-synuclein fibril core identifies a residue important for fibril nucleation: a possible implication for diagnostic applications.
alpha-Synuclein is one of the causative proteins of the neurodegenerative disorder, Parkinson's disease. Deposits of alpha-synuclein called Lewy bodies are a hallmark of this disorder, which is implicated in its progression. In order to understand the mechanism of amyloid fibril formation of alpha-synuclein in more detail, in this study we have isolated a specific, ~20 residue peptide region of the alpha-synuclein fibril core, using a combination of Edman degradation and mass-spectroscopy analyses of protease-resistant samples. Starting from this core peptide sequence, we then synthesized a series of peptides that undergo aggregation and fibril formation under similar conditions. Interestingly, in a derivative peptide where a crucial phenylalanine residue was changed to a glycine, the ability to initiate spontaneous fibril formation was abolished, while the ability to extend from preexisting fibril seeds was conserved. This fibril extension occurred irrespective of the source of the initial fibril seed, as demonstrated in experiments using fibril seeds of insulin, lysozyme, and GroES. This interesting ability suggests that this peptide might form the basis for a possible diagnostic tool useful in detecting the presence of various fibrillogenic factors.
Yagi
Hisashi
H
Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, Tottori 680-8552, Japan.
Takeuchi
Hideki
H
Ogawa
Shiho
S
Ito
Naomi
N
Sakane
Isao
I
Hongo
Kunihiro
K
Mizobata
Tomohiro
T
Goto
Yuji
Y
Kawata
Yasushi
Y
D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism*; D052160:Benzothiazoles; D002942:Circular Dichroism; D006801:Humans; D007328:Insulin / Q000737:chemistry / Q000378:metabolism; D016631:Lewy Bodies / Q000737:chemistry*; D018625:Microscopy, Atomic Force; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry* / Q000302:isolation & purification* / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism
D000682:Amyloid; D052160:Benzothiazoles; D007328:Insulin; D010446:Peptide Fragments; D013844:Thiazoles; D051844:alpha-Synuclein; C009462:thioflavin T