Imaging protein aggregates in the serum and cerebrospinal fluid in Parkinson's disease.
Imaging protein aggregates in the serum and cerebrospinal fluid in Parkinson's disease.
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帕金森病患者血清和脑脊液中成像蛋白聚集
DOI：
10.1093/brain/awab306
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发表时间：
2022-04-18
期刊：
影响因子：
14.5
通讯作者：
Klenerman, David
中科院分区：
文献类型：
--
作者：
Lobanova, Evgeniia;Whiten, Daniel;Ruggeri, Francesco S.;Taylor, Christopher G.;Kouli, Antonina;Xia, Zengjie;Emin, Derya;Zhang, Yu P.;Lam, Jeff Y. L.;Williams-Gray, Caroline H.;Klenerman, David
关键词：
α-突触核蛋白的聚集在帕金森病的发生发展中起着关键作用。可溶性聚集体不仅存在于人脑中，而且存在于CSF和血液中。表征这些生物流体中存在的聚集体可以提供对疾病机制的见解，并且还具有辅助诊断的潜力。我们使用了两种光学单分子成像方法，称为适配体DNA-PAINT和单聚集体共聚焦荧光，以及高分辨率原子力显微镜，用于特异性检测和表征具有分子间β折叠结构的单个聚集体，这些聚集体存在于15名早期帕金森病患者的CSF和血清中，与10名健康年龄匹配的对照组相比。我们在CSF和血清中都发现了大小为20 nm至200 nm的聚集体。帕金森病和对照组之间的聚集体大小分布存在差异，帕金森病患者血清中较大聚集体（长于150 nm）的数量显著增加。为了确定聚集体的化学组成，我们在11名早期帕金森病患者和10名对照受试者的独立队列中，在α-突触核蛋白和淀粉样蛋白-β免疫耗竭后对血清进行适体DNA-PAINT。帕金森病患者血清中的β-折叠聚集体平均由50%的α-突触核蛋白和50%的淀粉样蛋白-β组成，而对照血清中的α-突触核蛋白和淀粉样蛋白-β分别为30%和70%[这些聚集体的比例在患病组和对照组之间存在统计学显著差异（每个物种的P = 1.7 × 10−5）]。使用我们的超分辨率方法提取的血清中β-折叠α-突触核蛋白聚集体与β-折叠淀粉样蛋白-β聚集体的数量比区分帕金森病患者和对照组的准确率为98.2%（AUC = 98.2%，P = 4.3 × 10−5）。我们的数据表明，研究血清中存在的蛋白质聚集体可以提供有关帕金森病中蛋白质稳态破坏的信息，并作为疾病的潜在生物标志物进行进一步研究。使用一套新的生物物理学方法，Lobanova等人揭示了与对照组相比，帕金森病患者血清和CSF中单个α-突触核蛋白和淀粉样蛋白-β聚集体的组成和大小的变化，疾病中较大聚集体的比例较高，α-突触核蛋白/淀粉样蛋白-β比率增加。
Aggregation of α-synuclein plays a key role in the development of Parkinson’s disease. Soluble aggregates are present not only within human brain but also the CSF and blood. Characterizing the aggregates present in these biofluids may provide insights into disease mechanisms and also have potential for aiding diagnosis. We used two optical single-molecule imaging methods called aptamer DNA-PAINT and single-aggregate confocal fluorescence, together with high-resolution atomic force microscopy for specific detection and characterization of individual aggregates with intermolecular β-sheet structure, present in the CSF and serum of 15 early stage Parkinson’s disease patients compared to 10 healthy age-matched controls. We found aggregates ranging in size from 20 nm to 200 nm, in both CSF and serum. There was a difference in aggregate size distribution between Parkinson’s disease and control groups with a significantly increased number of larger aggregates (longer than 150 nm) in the serum of patients with Parkinson’s disease. To determine the chemical composition of the aggregates, we performed aptamer DNA-PAINT on serum following α-synuclein and amyloid-β immunodepletion in an independent cohort of 11 patients with early stage Parkinson’s disease and 10 control subjects. β-Sheet aggregates in the serum of Parkinson’s disease patients were found to consist of, on average, 50% α-synuclein and 50% amyloid-β in contrast to 30% α-synuclein and 70% amyloid-β in control serum [the differences in the proportion of these aggregates were statistically significant between diseased and control groups (P = 1.7 × 10−5 for each species)]. The ratio of the number of β-sheet α-synuclein aggregates to β-sheet amyloid-β aggregates in serum extracted using our super-resolution method discriminated Parkinson’s disease cases from controls with an accuracy of 98.2% (AUC = 98.2%, P = 4.3 × 10−5). Our data suggest that studying the protein aggregates present in serum can provide information about the disruption of protein homeostasis occurring in Parkinson’s disease and warrants further investigation as a potential biomarker of disease. Using a suite of new biophysical methods, Lobanova et al. reveal changes in the composition and size of individual α-synuclein and amyloid-β aggregates in the serum and CSF of patients with Parkinson's disease compared to controls, with a higher proportion of larger aggregates and an increased α-synuclein/amyloid-β ratio developing in disease.
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DOI：
10.1523/jneurosci.0203-11.2011
发表时间：
2011-05-04
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Li S;Jin M;Koeglsperger T;Shepardson NE;Shankar GM;Selkoe DJ
通讯作者：
Selkoe DJ
影响因子：
15.1
作者：
Majbour NK;Vaikath NN;van Dijk KD;Ardah MT;Varghese S;Vesterager LB;Montezinho LP;Poole S;Safieh-Garabedian B;Tokuda T;Teunissen CE;Berendse HW;van de Berg WD;El-Agnaf OM
通讯作者：
El-Agnaf OM
影响因子：
4.8
作者：
Danzer, Karin M.;Ruf, Wolfgang P.;McLean, Pamela J.
通讯作者：
McLean, Pamela J.
影响因子：
14.5
作者：
Roberts, Blaine R.;Lind, Monica;Masters, Colin L.
通讯作者：
Masters, Colin L.
影响因子：
7.4
作者：
Taylor, Christopher G.;Meisl, Georg;Klenerman, David
通讯作者：
Klenerman, David