A variety of cellular processes, including vesicle clustering in the presynaptic compartment, are impaired in Parkinson's disease and have been closely associated with α-synuclein oligomerization. Emerging evidence proves the existence of α-synuclein-related pathology in the peripheral nervous system, even though the presence of α-synuclein oligomers in situ in living patients remains poorly investigated. In this case-control study, we show previously undetected α-synuclein oligomers within synaptic terminals of autonomic fibres in skin biopsies by means of the proximity ligation assay and propose a procedure for their quantification (proximity ligation assay score). Our study revealed a significant increase in α-synuclein oligomers in consecutive patients with Parkinson's disease compared to consecutive healthy controls (P < 0.001). Proximity ligation assay score (threshold value > 96 using receiver operating characteristic) was found to have good sensitivity, specificity and positive predictive value (82%, 86% and 89%, respectively). Furthermore, to disclose the role of putative genetic predisposition in Parkinson's disease aetiology, we evaluated the differential accumulation of oligomers in a unique cohort of 19 monozygotic twins discordant for Parkinson's disease. The significant difference between patients and healthy subjects was confirmed in twins. Intriguingly, although no difference in median values was detected between consecutive healthy controls and healthy twins, the prevalence of healthy subjects positive for proximity ligation assay score was significantly greater in twins than in the consecutive cohort (47% versus 14%, P = 0.019). This suggests that genetic predisposition is important, but not sufficient, in the aetiology of the disease and strengthens the contribution of environmental factors. In conclusion, our data provide evidence that α-synuclein oligomers accumulate within synaptic terminals of autonomic fibres of the skin in Parkinson's disease for the first time. This finding endorses the hypothesis that α-synuclein oligomers could be used as a reliable diagnostic biomarker for Parkinson's disease. It also offers novel insights into the physiological and pathological roles of α-synuclein in the peripheral nervous system.

中文翻译：

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α-突触核蛋白低聚物在特发性和单卵双生帕金森氏病患者皮肤活检中的应用。

帕金森氏病会损害包括突触前区囊泡聚集在内的多种细胞过程，并与α-突触核蛋白寡聚密切相关。新兴证据证明，即使活患者体内原位存在α-突触核蛋白低聚物，对周围神经系统仍存在α-突触核蛋白相关病理学的研究。在此病例对照研究中，我们通过邻近结扎法显示了皮肤活检中自主神经纤维突触末端内先前未检测到的α-突触核蛋白低聚物，并提出了对其进行定量的程序（接近结扎法评分）。我们的研究表明，与连续健康对照组相比，帕金森氏病连续患者中α-突触核蛋白低聚物显着增加（P <0.001）。发现邻近结扎测定得分（使用接收器操作特征阈值> 96）具有良好的敏感性，特异性和阳性预测值（分别为82％，86％和89％）。此外，为了揭示帕金森氏病病因学中假定的遗传易感性的作用，我们评估了19名与帕金森氏病不符的单卵双胞胎的独特队列中寡聚体的差异积累。双胞胎证实了患者和健康受试者之间的显着差异。有趣的是，尽管连续健康对照者和健康双胞胎之间未检测到中位数差异，但双胞胎中邻近结扎分析得分阳性的健康受试者的患病率明显高于连续队列（47％比14％，P = 0.019） 。这表明遗传易感性在疾病的病因学中很重要，但还不够，并增强了环境因素的作用。总之，我们的数据提供了证据，表明α-突触核蛋白低聚物首次在帕金森氏病中的皮肤自主神经突触末端积累。这一发现证实了α-突触核蛋白低聚物可以用作帕金森氏病可靠诊断生物标记的假设。它还为α-突触核蛋白在周围神经系统中的生理和病理作用提供了新颖的见解。我们的数据提供了证据，表明α-突触核蛋白低聚物首次在帕金森氏病的皮肤自主神经纤维突触末端积累。这一发现证实了α-突触核蛋白低聚物可以用作帕金森氏病可靠诊断生物标记的假设。它还为α-突触核蛋白在周围神经系统中的生理和病理作用提供了新颖的见解。我们的数据提供了证据，表明α-突触核蛋白低聚物首次在帕金森氏病的皮肤自主神经纤维突触末端积累。这一发现证实了α-突触核蛋白低聚物可以用作帕金森氏病可靠诊断生物标记的假设。它还为α-突触核蛋白在周围神经系统中的生理和病理作用提供了新颖的见解。