期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
卷 1865, 期 6, 页码 1410-1420出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbadis.2019.02.013
关键词
Alpha-synuclein; Protein aggregation; Parkinson's disease; Amyloid fibrils; Interspecies difference
资金
- Japan Agency for Medical Research and Development, AMED [JP18dm0107140]
- Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan [17H01564, 15K06762, 17KT0131, 17J05799]
- 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
- Nanotechnology Platform Program (Synthesis of Molecules and Materials) of the MEXT
- Grants-in-Aid for Scientific Research [15K06762, 17KT0131, 17H01564, 17J05799] Funding Source: KAKEN
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 asyn 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.
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