Multiple system atrophy (MSA) is a debilitating and fatal neurodegenerative disorder. The disease severity warrants urgent development of disease-modifying therapy, but the disease pathogenesis is still enigmatic. Neurodegeneration in MSA brains is preceded by the emergence of glial cytoplasmic inclusions (GCIs), which are insoluble α-synuclein accumulations within oligodendrocytes (OLGs). Thus, preventive strategies against GCI formation may suppress disease progression. However, although numerous studies have tried to elucidate the molecular pathogenesis of GCI formation, difficulty remains in understanding the pathological interaction between the two pivotal aspects of GCIs; α-synuclein and OLGs. The difficulty originates from several enigmas: 1) what triggers the initial generation and possible propagation of pathogenic α-synuclein species? 2) what contributes to OLG-specific accumulation of α-synuclein, which is abundantly expressed in neurons but not in OLGs? and 3) how are OLGs and other glial cells affected and contribute to neurodegeneration? The primary pathogenesis of GCIs may involve myelin dysfunction and dyshomeostasis of the oligodendroglial cellular environment such as autophagy and iron metabolism. We have previously reported that oligodendrocyte precursor cells are more prone to develop intracellular inclusions in the presence of extracellular fibrillary α-synuclein. This finding implies a possibility that the propagation of GCI pathology in MSA brains is mediated through the internalization of pathological α-synuclein into oligodendrocyte precursor cells. In this review, in order to discuss the pathogenesis of GCIs, we will focus on the composition of neuronal and oligodendroglial inclusions in synucleinopathies. Furthermore, we will introduce some hypotheses on how α-synuclein pathology spreads among OLGs in MSA brains, in the light of our data from the experiments with primary oligodendrocyte lineage cell culture. While various reports have focused on the mysterious source of α-synuclein in GCIs, insights into the mechanism which regulates the uptake of pathological α-synuclein into oligodendroglial cells may yield the development of the disease-modifying therapy for MSA. The interaction between glial cells and α-synuclein is also highlighted with previous studies of post-mortem human brains, cultured cells, and animal models, which provide comprehensive insight into GCIs and the MSA pathomechanisms.

中文翻译：

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深入了解多系统萎缩的发病机理：关注神经胶质细胞质内含物。

多系统萎缩症（MSA）是一种使人衰弱和致命的神经退行性疾病。该疾病的严重性需要紧急开发改善疾病的疗法，但该疾病的发病机理仍是未知的。MSA大脑中的神经变性先于神经胶质细胞质内含物（GCI）的出现，它们是少突胶质细胞（OLG）中不可溶的α-突触核蛋白积聚。因此，针对GCI形成的预防策略可能会抑制疾病进展。然而，尽管许多研究试图阐明GCI形成的分子发病机制，但仍难以理解GCI的两个关键方面之间的病理相互作用。α-突触核蛋白和OLG。困难来自几个谜题：1）什么触发了致病性α-突触核蛋白物种的初始产生和可能的传播？2）是什么导致了α-突触核蛋白的OLG特异性积累，α-突触核蛋白在神经元中大量表达，但在OLG中却没有表达？3）OLG和其他神经胶质细胞如何受到影响并导致神经变性？GCI的主要发病机制可能涉及少突胶质细胞环境的髓磷脂功能障碍和动态平衡异常，例如自噬和铁代谢。我们以前曾报道过，少突胶质细胞前体细胞在存在细胞外原纤维α-突触核蛋白的情况下更倾向于发展细胞内包裹体。这一发现暗示了MSA大脑中GCI病理学传播是通过将病理性α-突触核蛋白内化为少突胶质前体细胞来介导的。在这篇评论中 为了讨论GCI的发病机理，我们将重点研究突触核蛋白病中神经元和少突胶质神经包涵体的组成。此外，根据原发性少突胶质细胞谱系细胞培养实验的数据，我们将介绍有关α-突触核蛋白病理学如何在MSA大脑中的OLG中传播的一些假设。虽然各种报道都集中在GCI中α-突触核蛋白的神秘来源，但对调节病理性α-突触核蛋白摄取到少突胶质细胞中的机制的见解可能会为MSA疾病改良疗法的发展提供参考。神经胶质细胞与α-突触核蛋白之间的相互作用在尸体后人类大脑，培养细胞和动物模型的先前研究中也得到了强调，这些研究提供了对GCI和MSA发病机制的全面了解。