Sequence- and seed-structure-dependent polymorphic fibrils of alpha-synuclein

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1865

Article

Tanaka, Goki¹  Yamanaka, Tomoyuki¹  Furukaw, Yoshiaki²  Kajimura, Naoko³  Mitsuoka, Kaoru³  Nukina, Nobuyuki¹ 

[1] Doshisha Univ, Grad Sch Brain Sci, Lab Struct Neuropathol, 1-3 Miyakodanitatara, Kyotanabe, Kyoto 6100394, Japan

[2] Keio Univ, Dept Chem, Lab Mech Chem Biomol, Kohoku Ku, 3-14-1 Hiyoshi, Yokohama, Kanagawa 2238522, Japan

[3] Osaka Univ, Res Ctr Ultra High Voltage Electron Microscopy, 7-1 Mihogaoka, Osaka 5670047, Japan

关键词: Alpha-synuclein;    Protein aggregation;    Parkinson's disease;    Amyloid fibrils;    Interspecies difference;   

DOI  :  10.1016/j.bbadis.2019.02.013

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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