Single-Molecule Detection of α-Synuclein Oligomers in Parkinson's Disease Patients Using Nanopores.
Single-Molecule Detection of α-Synuclein Oligomers in Parkinson's Disease Patients Using Nanopores.
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DOI：
10.1021/acsnano.3c08456
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发表时间：
2023-11-28
期刊：
影响因子：
17.1
通讯作者：
Ivanov, Aleksandar P.
中科院分区：
文献类型：
--
作者：
Liu, Yaxian;Wang, Xiaoyi;Campolo, Giulia;Teng, Xiangyu;Ying, Liming;Edel, Joshua B.;Ivanov, Aleksandar P.
关键词：
α-突触核蛋白（α-Synuclein，α-Syn）是一种内在无序的蛋白质，其在脑内的聚集与帕金森病（Parkinson's disease，PD）密切相关。除了大脑之外，α-突触核蛋白的寡聚体还存在于脑脊液（CSF）和血液中，对这些聚集体的分析可以提供诊断途径，并使人们能够更好地了解疾病机制。然而，由于α-Syn的蛋白质大小和形状不均匀，而且临床样本中的丰度较低，因此检测CSF和血液中的α-Syn具有挑战性。纳米孔技术为检测溶液中的单一蛋白质提供了一种有前途的途径;然而，该方法在复杂的生物流体中往往缺乏必要的选择性，其中存在多种背景生物分子。我们通过开发一种策略来解决这些限制，该策略将基于纳米孔的传感与分子载体相结合，可以特异性捕获尺寸小于20 nm的α-Syn寡聚体。我们证明，α-突触核蛋白寡聚体可以直接在临床样本中检测到，最小的样品处理，通过它们的离子电流特性，并成功地利用这种技术来区分PD患者队列和健康对照。测量结果表明，检测CSF中存在的α-Syn寡聚体可能为帕金森病的进展和监测提供有价值的见解。
α-Synuclein (α-Syn) is an intrinsically disordered protein whose aggregation in the brain has been significantly implicated in Parkinson’s disease (PD). Beyond the brain, oligomers of α-Synuclein are also found in cerebrospinal fluid (CSF) and blood, where the analysis of these aggregates may provide diagnostic routes and enable a better understanding of disease mechanisms. However, detecting α-Syn in CSF and blood is challenging due to its heterogeneous protein size and shape, and low abundance in clinical samples. Nanopore technology offers a promising route for the detection of single proteins in solution; however, the method often lacks the necessary selectivity in complex biofluids, where multiple background biomolecules are present. We address these limitations by developing a strategy that combines nanopore-based sensing with molecular carriers that can specifically capture α-Syn oligomers with sizes of less than 20 nm. We demonstrate that α-Synuclein oligomers can be detected directly in clinical samples, with minimal sample processing, by their ion current characteristics and successfully utilize this technology to differentiate cohorts of PD patients from healthy controls. The measurements indicate that detecting α-Syn oligomers present in CSF may potentially provide valuable insights into the progression and monitoring of Parkinson’s disease.
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