Conversion of wild-type alpha-synuclein into mutant-type fibrils and its propagation in the presence of A30P mutant.
Fibrillization or conformational change of alpha-synuclein is central in the pathogenesis of alpha-synucleinopathies, such as Parkinson disease. We found that the A30P mutant accelerates nucleation-dependent fibrillization of wild type (WT) alpha-synuclein. Electron microscopy observation and ultracentrifugation experiments revealed that shedding of fragments occurs from A30P fibrils and that these fragments accelerate fibrillization by serving as seeds. Immunochemical analysis using epitope-specific antibodies and biochemical analyses of protease-resistant cores demonstrated that A30P fibrils have a distinct conformation. Interestingly, WT fibrils formed with A30P seeds exhibited the same character as A30P fibrils, as did A30P fibrils formed with WT seeds, indicating that the A30P mutation affects the conformation and fibrillization of both WT and A30P. These effects of A30P mutation may explain the apparent conflict between the association of A30P with Parkinson disease and the slow fibrillization of A30P itself and therefore provide new insight into the molecular mechanisms of alpha-synucleinopathies.
Yonetani
Motokuni
M
Department of Molecular Neurobiology, Tokyo Institute of Psychiatry, 2-1-8 Kamikitazawa, Setagaya-ku, 156-8585 Tokyo, Japan.
Nonaka
Takashi
T
Masuda
Masami
M
Inukai
Yuki
Y
Oikawa
Takayuki
T
Hisanaga
Shin-Ichi
S
Hasegawa
Masato
M
D019943:Amino Acid Substitution; D000906:Antibodies / Q000737:chemistry*; D000939:Epitopes / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D020125:Mutation, Missense; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D020836:Protein Structure, Quaternary / Q000235:genetics; D051844:alpha-Synuclein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
D000906:Antibodies; D000939:Epitopes; D051844:alpha-Synuclein