Multiple System Atrophy is characterized pathologically by the accumulation of alpha-synuclein (aSyn) into glial cytoplasmic inclusions (GCIs). The mechanism underlying the formation of GCIs is not well understood. In this study, correlative light and electron microscopy was employed to investigate aSyn pathology in the substantia nigra and putamen of post-mortem multiple system atrophy brain donors. Three distinct types of aSyn immuno-positive inclusions were identified in oligodendrocytes, neurons and dark cells presumed to be dark microglia. Oligodendrocytes contained fibrillar GCIs that were consistently enriched with lysosomes and peroxisomes, supporting the involvement of the autophagy pathway in aSyn aggregation in multiple system atrophy. Neuronal cytoplasmic inclusions exhibited ultrastructural heterogeneity resembling both fibrillar and membranous inclusions, linking multiple systems atrophy and Parkinson’s disease. The novel aSyn pathology identified in the dark cells, displayed GCI-like fibrils or non-GCI-like ultrastructures suggesting various stages of aSyn accumulation in these cells. The observation of GCI-like fibrils within dark cells suggests these cells may be an important contributor to the origin or spread of pathological aSyn in multiple system atrophy. Our results suggest a complex interplay between multiple cell types that may underlie the formation of aSyn pathology in multiple system atrophy brain and highlight the need for further investigation into cell-specific disease pathologies in multiple system atrophy.

中文翻译：

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多系统萎缩中神经胶质和神经元α-突触核蛋白包涵体的独特超微结构表型

多系统萎缩的病理特征是α-突触核蛋白（aSyn）积累到神经胶质细胞质内含物（GCI）中。 GCI 形成的机制尚不清楚。在这项研究中，采用相关光学和电子显微镜来研究死后多系统萎缩脑供体的黑质和壳核的 aSyn 病理学。在少突胶质细胞、神经元和推测为暗小胶质细胞的暗细胞中鉴定出三种不同类型的 aSyn 免疫阳性包涵体。少突胶质细胞含有纤维状 GCI，这些 GCI 始终富含溶酶体和过氧化物酶体，支持自噬途径参与多系统萎缩中的 aSyn 聚集。神经元细胞质内含物表现出类似于纤维状和膜状内含物的超微结构异质性，将多个系统萎缩和帕金森病联系起来。在暗细胞中发现的新型 aSyn 病理学显示出 GCI 样原纤维或非 GCI 样超微结构，表明这些细胞中 aSyn 积累的各个阶段。对暗细胞内 GCI 样原纤维的观察表明，这些细胞可能是多系统萎缩中病理性 aSyn 的起源或传播的重要贡献者。我们的结果表明多种细胞类型之间复杂的相互作用可能是多系统萎缩脑中aSyn病理学形成的基础，并强调需要进一步研究多系统萎缩中的细胞特异性疾病病理学。