Parkinson’s disease (PD) is a neurodegenerative disorder whose diagnosis is often challenging because symptoms may overlap with neurodegenerative parkinsonisms. PD is characterized by intraneuronal accumulation of abnormal α-synuclein in brainstem while neurodegenerative parkinsonisms might be associated with accumulation of either α-synuclein, as in the case of Multiple System Atrophy (MSA) or tau, as in the case of Corticobasal Degeneration (CBD) and Progressive Supranuclear Palsy (PSP), in other disease-specific brain regions. Definite diagnosis of all these diseases can be formulated only neuropathologically by detection and localization of α-synuclein or tau aggregates in the brain. Compelling evidence suggests that trace-amount of these proteins can appear in peripheral tissues, including receptor neurons of the olfactory mucosa (OM). We have set and standardized the experimental conditions to extend the ultrasensitive Real Time Quaking Induced Conversion (RT-QuIC) assay for OM analysis. In particular, by using human recombinant α-synuclein as substrate of reaction, we have assessed the ability of OM collected from patients with clinical diagnoses of PD and MSA to induce α-synuclein aggregation, and compared their seeding ability to that of OM samples collected from patients with clinical diagnoses of CBD and PSP. Our results showed that a significant percentage of MSA and PD samples induced α-synuclein aggregation with high efficiency, but also few samples of patients with the clinical diagnosis of CBD and PSP caused the same effect. Notably, the final RT-QuIC aggregates obtained from MSA and PD samples owned peculiar biochemical and morphological features potentially enabling their discrimination. Our study provide the proof-of-concept that olfactory mucosa samples collected from patients with PD and MSA possess important seeding activities for α-synuclein. Additional studies are required for (i) estimating sensitivity and specificity of the technique and for (ii) evaluating its application for the diagnosis of PD and neurodegenerative parkinsonisms. RT-QuIC analyses of OM and cerebrospinal fluid (CSF) can be combined with the aim of increasing the overall diagnostic accuracy of these diseases, especially in the early stages.

中文翻译：

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帕金森病和多系统萎缩患者嗅粘膜样本中 α-突触核蛋白的高效 RT-QuIC 播种活性

帕金森病 (PD) 是一种神经退行性疾病，其诊断通常具有挑战性，因为症状可能与神经退行性帕金森病重叠。PD 的特征是脑干中异常 α-突触核蛋白的神经元内积累，而神经退行性帕金森综合征可能与 α-突触核蛋白的积累有关，如多系统萎缩 (MSA) 或 tau，如皮质基底节变性 (CBD) ) 和进行性核上性麻痹 (PSP)，在其他特定疾病的大脑区域。所有这些疾病的明确诊断只能通过检测和定位大脑中的 α-突触核蛋白或 tau 聚集体来进行神经病理学。令人信服的证据表明，微量的这些蛋白质可以出现在外周组织中，包括嗅粘膜 (OM) 的受体神经元。我们已经设置并标准化了实验条件，以扩展用于 OM 分析的超灵敏实时振动诱导转换 (RT-QuIC) 测定。特别是，通过使用人重组α-突触核蛋白作为反应底物，我们评估了从临床诊断为 PD 和 MSA 的患者中收集的 OM 诱导 α-突触核蛋白聚集的能力，并将它们的播种能力与收集的 OM 样本进行比较来自临床诊断为 CBD 和 PSP 的患者。我们的研究结果表明，很大比例的 MSA 和 PD 样本高效诱导 α-突触核蛋白聚集，但临床诊断为 CBD 和 PSP 的患者样本也很少引起相同的效果。尤其，从 MSA 和 PD 样品中获得的最终 RT-QuIC 聚集体具有独特的生化和形态特征，可能使其能够进行区分。我们的研究提供了概念验证，即从 PD 和 MSA 患者收集的嗅觉粘膜样本对 α-突触核蛋白具有重要的播种活性。需要额外的研究来 (i) 评估该技术的敏感性和特异性，以及 (ii) 评估其在诊断 PD 和神经退行性帕金森病中的应用。OM 和脑脊液 (CSF) 的 RT-QuIC 分析可以与提高这些疾病的整体诊断准确性的目的相结合，尤其是在早期阶段。我们的研究提供了概念验证，即从 PD 和 MSA 患者收集的嗅觉粘膜样本对 α-突触核蛋白具有重要的播种活性。需要额外的研究来 (i) 评估该技术的敏感性和特异性，以及 (ii) 评估其在诊断 PD 和神经退行性帕金森病中的应用。OM 和脑脊液 (CSF) 的 RT-QuIC 分析可以与提高这些疾病的整体诊断准确性的目的相结合，尤其是在早期阶段。我们的研究提供了概念验证，即从 PD 和 MSA 患者收集的嗅觉粘膜样本对 α-突触核蛋白具有重要的播种活性。需要额外的研究来 (i) 评估该技术的敏感性和特异性，以及 (ii) 评估其在诊断 PD 和神经退行性帕金森病中的应用。OM 和脑脊液 (CSF) 的 RT-QuIC 分析可以与提高这些疾病的整体诊断准确性的目的相结合，尤其是在早期阶段。