Nanoscale imaging of individual amyloid aggregates extracted from brains of Alzheimer and Parkinson patients reveals presence of lipids in α-synuclein but not in amyloid β1-42 fibrils.
Nanoscale imaging of individual amyloid aggregates extracted from brains of Alzheimer and Parkinson patients reveals presence of lipids in α-synuclein but not in amyloid β1-42 fibrils.
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从阿尔茨海默病和帕金森病患者大脑中提取的单个淀粉样蛋白聚集体的纳米级成像揭示了α-突触核蛋白中存在脂质，但淀粉样蛋白β1-42 原纤维中不存在脂质。
DOI：
10.1002/pro.4598
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Kurouski,Dmitry
中科院分区：
文献类型：
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作者：
Zhaliazka,Kiryl;Kurouski,Dmitry
错误折叠蛋白质的突然聚集是阿尔茨海默病（AD）和帕金森病（PD）的潜在分子原因。AD和PD都是影响世界各地数百万人的严重疾病。一种小的42个氨基酸长的肽，称为淀粉样蛋白β（Aβ），在AD患者的额叶皮质中聚集，形成寡聚体和原纤维，这是一种高毒性蛋白质聚集体，可导致进行性神经元死亡。在PD患者的中脑、下丘脑和丘脑中观察到类似的α-突触核蛋白（α-Syn）聚集体，α-Syn是一种促进神经递质释放的小蛋白质。在这项研究中，我们利用创新的纳米红外成像技术来研究分别从AD和PD患者的大脑中提取的单个Aβ和α-syn纤维的结构组织。我们在每个患者的大脑中观察到两种形态学上不同的Aβ和α-Syn纤维多晶型物。一个具有扭曲拓扑结构，而另一个表现出扁平带状形态。我们发现两种多晶型物具有相同的平行β折叠主导的二级结构。这些结果表明，两种原纤维多晶型物均由结构相似（如果不相同）的细丝构建，这些细丝盘绕形成扭曲原纤维或在直Aβ和α-Syn原纤维的情况下并排相关。单个蛋白质聚集体的纳米红外分析还显示，扭曲和带状α-Syn原纤维结构中存在脂质，而在任何Aβ原纤维多晶型物中均未观察到脂质。这些研究结果表明，脂膜可以在PD的发病和进展中发挥至关重要的作用。
Abrupt aggregation of misfolded proteins is the underlying molecular cause of Alzheimer disease (AD) and Parkinson disease (PD). Both AD and PD are severe pathologies that affect millions of people around the world. A small 42 amino acid long peptide, known as amyloid β (Aβ), aggregates in the frontal cortex of AD patients forming oligomers and fibrils, highly toxic protein aggregates that cause progressive neuron death. Similar aggregates of α‐synuclein (α‐Syn), a small protein that facilitates neurotransmitter release, are observed in the midbrain, hypothalamus, and thalamus of people with PD. In this study, we utilized the innovative nano‐Infrared imaging technique to investigate the structural organization of individual Aβ and α‐syn fibrilspostmortemextracted from brains of AD and PD patients, respectively. We observed two morphologically different Aβ and α‐Syn fibril polymorphs in each patient's brain. One had twisted topology, whereas another exhibited flat tape‐like morphology. We found that both polymorphs shared the same parallel β‐sheet‐dominated secondary structure. These findings suggested that both fibril polymorphs were built from structurally similar if not identical filaments that coiled forming twisted fibrils or associated side‐by‐side in the case of straight Aβ and α‐Syn fibrils. Nano‐Infrared analysis of individual protein aggregates also revealed the presence of lipids in the structure of both twisted and tape‐like α‐Syn fibrils that were not observed in any of the Aβ fibril polymorphs. These findings demonstrate that lipid membranes can play a critically important role in the onset and progression of PD.