Phosphorylated α-synuclein in skin Schwann cells: a new biomarker for multiple system atrophy
Phosphorylated α-synuclein in skin Schwann cells: a new biomarker for multiple system atrophy
复制标题
DOI：
10.1093/brain/awac124
复制
发表时间：
2022-05-12
期刊：
影响因子：
14.5
通讯作者：
Liguori, Rocco
中科院分区：
文献类型：
--
作者：
Donadio, Vincenzo;Incensi, Alex;Liguori, Rocco
多系统萎缩(MSA)是以脑内神经胶质细胞胞质包涵体形式的磷酸化α-突触核蛋白(p-syn)积聚为特征的疾病，迫切需要一种针对这种疾病的特异性生物标志物。我们旨在研究p-SYN是否也可以作为雪旺细胞胞浆包涵体(SCCI)在皮肤残留的非髓鞘雪旺细胞(RSCs)中检测到，并且可能是MSA的一个可靠的临床生物标志物。这项横断面诊断研究评估了96例患者的皮肤p-SYN：46例疑似MSA(29例帕金森病型MSA和17例小脑型MSA)，34例帕金森病(PD)和16例路易体痴呆(DLB)。我们还包括50名健康对照受试者。患者是从五个不同的医疗中心招募的。皮肤切片中的P-SYN聚集体用免疫荧光染色，然后用共聚焦显微镜和免疫电子显微镜进行分析。所有的分析都是以盲法进行的。总体而言，78%的MSA患者和100%的PD/DLB患者中发现了p-syn聚集体，而在对照组中检测不到。至于神经元集合体，78%的MSA患者的体神经元p-syn阳性，而所有PD/DLB患者的自主神经神经元p-syn阳性。当分析RSCs中p-syn的存在时，74%的MSA患者呈阳性，而在PD/DLB患者中未观察到这种SCCI。免疫电子显微镜分析证实，SCCI仅见于MSA患者，因此在PD/DB患者中不存在。综上所述，我们的研究结果表明：(I)RSC中的p-syn纤维是MSA的一个病理标志，可作为一种特异和敏感的疾病生物标志物；(Ii)在路易体突触核病(PD/DLB)中，只有神经元含有p-syn的沉积；(Iii)p-syn在皮肤中的细胞特异性沉积在许多方面反映了脑的情况，提示无髓鞘胶质细胞也参与了MSA的发病机制。
Multiple system atrophy (MSA) is characterized by accumulation of phosphorylated alpha-synuclein (p-syn) as glial cytoplasmic inclusions in the brain and a specific biomarker for this disorder is urgently needed. We aimed at investigating if p-syn can also be detected in skin Remak non-myelinating Schwann cells (RSCs) as Schwann cell cytoplasmic inclusions (SCCi) and may represent a reliable clinical biomarker for MSA.This cross-sectional diagnostic study evaluated skin p-syn in 96 patients: 46 with probable MSA (29 with parkinsonism type MSA and 17 with cerebellar type MSA), 34 with Parkinson's disease (PD) and 16 with dementia with Lewy bodies (DLB). We also included 50 healthy control subjects. Patients were recruited from five different medical centres. P-syn aggregates in skin sections were stained by immunofluorescence, followed by analyses with confocal microscopy and immuno-electron microscopy. All analyses were performed in a blinded fashion.Overall, p-syn aggregates were found in 78% of MSA patients and 100% of patients with PD/DLB, whereas they could not be detected in controls. As for neuronal aggregates 78% of MSA patients were positive for p-syn in somatic neurons, whereas all PD/DLB patients were positive in autonomic neurons. When analysing the presence of p-syn in RSCs, 74% of MSA patients were positive, whereas no such SCCi could be observed in PD/DLB patients. Analyses by immuno-electron microscopy confirmed that SCCi were only found in cases with MSA and thus absent in those with PD/DLB.In conclusion, our findings demonstrate that (i) fibrillar p-syn in RSCs is a pathological hallmark of MSA and may be used as a specific and sensitive disease biomarker; (ii) in Lewy body synucleinopathies (PD/DLB) only neurons contain p-syn deposits; and (iii) the cell-specific deposition of p-syn in the skin thus mirrors that of the brain in many aspects and suggests that non-myelinated glial cells are also involved in the MSA pathogenesis.