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Structures of a-synuclein filaments from multiple system atrophy

机译：来自多系统萎缩的A-突触核蛋白长丝的结构

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摘要

Synucleinopathies, which include multiple system atrophy (MSA), Parkinson's disease, Parkinson's disease with dementia and dementia with Lewy bodies (DLB), are human neurodegenerative diseases(1). Existing treatments are at best symptomatic. These diseases are characterized by the presence of, and believed to be caused by the formation of, filamentous inclusions of alpha-synuclein in brain cells(,)(2)(3). However, the structures of alpha-synuclein filaments from the human brain are unknown. Here, using cryo-electron microscopy, we show that alpha-synuclein inclusions from the brains of individuals with MSA are made of two types of filament, each of which consists of two different protofilaments. In each type of filament, non-proteinaceous molecules are present at the interface of the two protofilaments. Using two-dimensional class averaging, we show that alpha-synuclein filaments from the brains of individuals with MSA differ from those of individuals with DLB, which suggests that distinct conformers or strains characterize specific synucleinopathies. As is the case with tau assemblies(4-9), the structures of alpha-synuclein filaments extracted from the brains of individuals with MSA differ from those formed in vitro using recombinant proteins, which has implications for understanding the mechanisms of aggregate propagation and neurodegeneration in the human brain. These findings have diagnostic and potential therapeutic relevance, especially because of the unmet clinical need to be able to image filamentous alpha-synuclein inclusions in the human brain.
机译：包括多种系统萎缩（MSA），帕金森病，帕金森病与痴呆症和痴呆症的痴呆症（DLB）是人类神经变性疾病（1）。现有的治疗是最好的症状。这些疾病的特征在于存在，并且据信由脑细胞（）（2）（3）中的α-突触核蛋白的形成丝状夹杂物引起。然而，来自人脑的α-突触核蛋白长丝的结构是未知的。这里，使用低温电子显微镜检查，我们表明来自MSA的个体大脑的α-突触核蛋白夹杂物由两种类型的丝制成，每个丝由两种不同的原美丝组成。在每种类型的长丝中，存在非蛋白质分子在两个原子丝的界面处存在。使用二维等级平均，我们表明来自MSA的个体大脑的α-突触核蛋白长丝与DLB的个体的血管不同，这表明不同的符合子或菌株表征特异性同步素病变。与Tau组件（4-9）的情况一样，由MSA的个体大脑中提取的α-突触核蛋白长丝的结构与使用重组蛋白质的体外形成的结构不同，这具有了解综合繁殖和神经变性机制的影响在人的大脑中。这些发现具有诊断和潜在的治疗相关性，尤其是因为未掩盖的临床需要能够在人脑中成像丝状α-突出核蛋白夹杂物。

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  • 来源
    《Nature》 |2020年第7825期|464-469|共6页
  • 作者

    Schweighauser Manuel; Shi Yang; Tarutani Airi; Kametani Fuyuki; Murzin Alexey G.; Ghetti Bernardino; Matsubara Tomoyasu; Tomita Taisuke; Ando Takashi; Hasegawa Kazuko; Murayama Shigeo; Yoshida Mari; Hasegawa Masato; Scheres Sjors H. W.; Goedert Michel;

  • 作者单位

    MRC Lab Mol Biol Cambridge England;

    MRC Lab Mol Biol Cambridge England;

    Tokyo Metropolitan Inst Med Sci Dept Brain & Neurosci Tokyo Japan|Univ Tokyo Grad Sch Pharmaceut Sci Tokyo Japan;

    Tokyo Metropolitan Inst Med Sci Dept Brain & Neurosci Tokyo Japan;

    MRC Lab Mol Biol Cambridge England;

    Indiana Univ Sch Med Dept Pathol & Lab Med Indianapolis IN 46202 USA;

    Tokyo Metropolitan Inst Gerontol Dept Neuropathol Tokyo Japan;

    Univ Tokyo Grad Sch Pharmaceut Sci Tokyo Japan;

    Nagoya Univ Dept Neurol Grad Sch Med Nagoya Aichi Japan;

    Sagamihara Natl Hosp Div Neurol Sagamihara Kanagawa Japan;

    Tokyo Metropolitan Inst Gerontol Dept Neuropathol Tokyo Japan;

    Aichi Med Univ Inst Med Sci Aging Nagakute Aichi Japan;

    Tokyo Metropolitan Inst Med Sci Dept Brain & Neurosci Tokyo Japan;

    MRC Lab Mol Biol Cambridge England;

    MRC Lab Mol Biol Cambridge England;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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