Sequence- and seed-structure-dependent polymorphic fibrils of alpha-synuclein
Sequence- and seed-structure-dependent polymorphic fibrils of alpha-synuclein
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DOI：
10.1016/j.bbadis.2019.02.013
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发表时间：
2019-06-01
影响因子：
6.2
通讯作者：
Nukina, Nobuyuki
中科院分区：
文献类型：
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作者：
Tanaka, Goki;Yamanaka, Tomoyuki;Nukina, Nobuyuki
突触核蛋白病包括一组不同的神经退行性疾病，包括帕金森病（PD）、路易体痴呆和多系统萎缩。它们有一个共同的病理学特征，即α-突触核蛋白（α-syn）在神经元或少突胶质细胞中的沉积。A-syn在脊椎动物中高度保守，但小鼠a-syn的一级序列与人类的一级序列在七个位置上不同。然而，其总量的结构差异仍有待充分表征。在这项研究中，我们发现，人类和小鼠的asyn聚集在体外形成形态上不同的淀粉样纤维，分别表现出扭曲和直的结构。此外，我们在人和小鼠a-syn聚集体中鉴定了不同的蛋白酶抗性核心区，长的和短的。有趣的是，在7个不保守的氨基酸中，只有家族性PD突变之一的A53 T取代负责结构转换为直型。最后，我们检查了结构差异是否可通过接种传递，并发现用A53 T聚集体接种的人a-syn形成具有短蛋白酶抗性核心的直型原纤维。这些结果表明，α-syn聚集体在自发聚集时形成序列依赖性多态性原纤维，但在接种时变成种子结构依赖性的。
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.