TY - JOUR
T1 - Sequence- and seed-structure-dependent polymorphic fibrils of alpha-synuclein
AU - Tanaka, Goki
AU - Yamanaka, Tomoyuki
AU - Furukawa, Yoshiaki
AU - Kajimura, Naoko
AU - Mitsuoka, Kaoru
AU - Nukina, Nobuyuki
N1 - Funding Information:
The authors thank Edward William Ko Uy for English editing of the manuscript, and Sakiko Fujita (NAIST, Nara, Japan) for technical support. We thank the Support Unit for Bio-Material Analysis, RIKEN BSI Research Resources Center, especially Aya Abe and Kaori Otsuki for mass spectrometric analysis. We also thank the Doshisha University Faculty of Life and Medical Sciences, especially Junko Naritomi, for DNA sequencing. This work was supported by Japan Agency for Medical Research and Development, AMED under Grant Number JP18dm0107140 to N.N and from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan to N.N. (17H01564), to T.Y. (15K06762, 17KT0131) and to G.T. (17J05799). A part of this work was supported by Advanced Characterization Nanotechnology Platform, Nanotechnology Platform Program of MEXT, Japan at the Research Center for Ultra-High Voltage Electron Microscopy (Nanotechnology Open Facilities) in Osaka University. A part of this work was conducted in NAIST, supported by Nanotechnology Platform Program (Synthesis of Molecules and Materials) of the MEXT.
Funding Information:
The authors thank Edward William Ko Uy for English editing of the manuscript, and Sakiko Fujita (NAIST, Nara, Japan) for technical support. We thank the Support Unit for Bio-Material Analysis, RIKEN BSI Research Resources Center, especially Aya Abe and Kaori Otsuki for mass spectrometric analysis. We also thank the Doshisha University Faculty of Life and Medical Sciences, especially Junko Naritomi, for DNA sequencing. This work was supported by Japan Agency for Medical Research and Development , AMED under Grant Number JP18dm0107140 to N.N and from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan to N.N. ( 17H01564 ), to T.Y. ( 15K06762 , 17KT0131 ) and to G.T. ( 17J05799 ). A part of this work was supported by Advanced Characterization Nanotechnology Platform, Nanotechnology Platform Program of MEXT, Japan at the Research Center for Ultra-High Voltage Electron Microscopy (Nanotechnology Open Facilities) in Osaka University . A part of this work was conducted in NAIST, supported by Nanotechnology Platform Program (Synthesis of Molecules and Materials) of the MEXT.
Publisher Copyright:
© 2019 Elsevier B.V.
PY - 2019/6/1
Y1 - 2019/6/1
N2 - Synucleinopathies comprise a diverse group of neurodegenerative diseases including Parkinson's disease (PD), dementia with Lewy bodies, and multiple system atrophy. These share a common pathological feature, the deposition of alpha-synuclein (a-syn) in neurons or oligodendroglia. A-syn is highly conserved in vertebrates, but the primary sequence of mouse a-syn differs from that of human at seven positions. However, structural differences of their aggregates remain to be fully characterized. In this study, we found that human and mouse a-syn aggregated in vitro formed morphologically distinct amyloid fibrils exhibiting twisted and straight structures, respectively. Furthermore, we identified different protease-resistant core regions, long and short, in human and mouse a-syn aggregates. Interestingly, among the seven unconserved amino acids, only A53T substitution, one of the familial PD mutations, was responsible for structural conversion to the straight-type. Finally, we checked whether the structural differences are transmissible by seeding and found that human a-syn seeded with A53T aggregates formed straight-type fibrils with short protease-resistant cores. These results suggest that a-syn aggregates form sequence-dependent polymorphic fibrils upon spontaneous aggregation but become seed structure-dependent upon seeding.
AB - Synucleinopathies comprise a diverse group of neurodegenerative diseases including Parkinson's disease (PD), dementia with Lewy bodies, and multiple system atrophy. These share a common pathological feature, the deposition of alpha-synuclein (a-syn) in neurons or oligodendroglia. A-syn is highly conserved in vertebrates, but the primary sequence of mouse a-syn differs from that of human at seven positions. However, structural differences of their aggregates remain to be fully characterized. In this study, we found that human and mouse a-syn aggregated in vitro formed morphologically distinct amyloid fibrils exhibiting twisted and straight structures, respectively. Furthermore, we identified different protease-resistant core regions, long and short, in human and mouse a-syn aggregates. Interestingly, among the seven unconserved amino acids, only A53T substitution, one of the familial PD mutations, was responsible for structural conversion to the straight-type. Finally, we checked whether the structural differences are transmissible by seeding and found that human a-syn seeded with A53T aggregates formed straight-type fibrils with short protease-resistant cores. These results suggest that a-syn aggregates form sequence-dependent polymorphic fibrils upon spontaneous aggregation but become seed structure-dependent upon seeding.
KW - Alpha-synuclein
KW - Amyloid fibrils
KW - Interspecies difference
KW - Parkinson's disease
KW - Protein aggregation
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U2 - 10.1016/j.bbadis.2019.02.013
DO - 10.1016/j.bbadis.2019.02.013
M3 - Article
C2 - 30790619
AN - SCOPUS:85061932736
VL - 1865
SP - 1410
EP - 1420
JO - Biochimica et Biophysica Acta - Molecular Basis of Disease
JF - Biochimica et Biophysica Acta - Molecular Basis of Disease
SN - 0925-4439
IS - 6
ER -
