Multiple system atrophy (MSA) is pathologically characterized by the presence of fibrillar α-synuclein-immunoreactive inclusions in oligodendrocytes. Although the myelinating process of oligodendrocytes can be observed in adult human brains, little is known regarding the presence of α-synuclein pathology in immature oligodendrocytes and how their maturation and myelination are affected in MSA brains. Recently, breast carcinoma amplified sequence 1 (BCAS1) has been found to be specifically expressed in immature oligodendrocytes undergoing maturation and myelination. Here, we analyzed the altered dynamics of oligodendroglial maturation in both MSA brains and primary oligodendroglial cell cultures which were incubated with α-synuclein pre-formed fibrils. The numbers of BCAS1-expressing oligodendrocytes that displayed a matured morphology negatively correlated with the density of pathological inclusions in MSA brains but not with that in Parkinson’s disease and diffuse Lewy body disease. In addition, a portion of the BCAS1-expressing oligodendrocyte population showed cytoplasmic inclusions, which were labeled with antibodies against phosphorylated α-synuclein and cleaved caspase-9. Further in vitro examination indicated that the α-synuclein pre-formed fibrils induced cytoplasmic inclusions in the majority of BCAS1-expressing oligodendrocytes. In contrast, the majority of BCAS1-non-expressing mature oligodendrocytes did not develop inclusions on day 4 after maturation induction. Furthermore, exposure of α-synuclein pre-formed fibrils in the BCAS1-positive phase caused a reduction in oligodendroglial cell viability. Our results indicated that oligodendroglial maturation and myelination are impaired in the BCAS1-positive phase of MSA brains, which may lead to the insufficient replacement of defective oligodendrocytes. In vitro, the high susceptibility of BCAS1-expressing primary oligodendrocytes to the extracellular α-synuclein pre-formed fibrils suggests the involvement of insufficient oligodendroglial maturation in MSA disease progression and support the hypothesis that the BCAS1-positive oligodendrocyte lineage cells are prone to take up aggregated α-synuclein in vivo.

中文翻译：

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BCAS1阳性未成熟少突胶质细胞受α-突触核蛋白诱导的多系统萎缩病理的影响。

多系统萎缩症（MSA）的病理特征是少突胶质细胞中存在纤维状α-突触核蛋白-免疫反应性内含物。尽管可以在成人的大脑中观察到少突胶质细胞的髓鞘形成过程，但对于未成熟的少突胶质细胞中α-突触核蛋白的病理学及其在MSA大脑中的成熟和髓鞘化如何受到影响知之甚少。最近，已发现乳腺癌扩增序列1（BCAS1）在经历成熟和髓鞘形成的未成熟少突胶质细胞中特异性表达。在这里，我们分析了MSA大脑和原发性少突胶质细胞培养物（与α-突触核蛋白预先形成的原纤维一起孵育）中少突胶质成熟的变化动力学。表现出成熟形态的表达BCAS1的少突胶质细胞的数量与MSA脑中病理性包涵体的密度呈负相关，而与帕金森氏病和弥漫性路易体病的数量则不相关。另外，表达BCAS1的少突胶质细胞群的一部分显示出胞质内含物，这些内含物被抗磷酸化的α-突触核蛋白和裂解的胱天蛋白酶9的抗体标记。进一步的体外检查表明，α-突触核蛋白预先形成的原纤维在大多数表达BCAS1的少突胶质细胞中诱导了胞质内含物。相比之下，大多数不表达BCAS1的成熟少突胶质细胞在诱导成熟后第4天没有形成包涵体。此外，在BCAS1阳性阶段，α-突触核蛋白预先形成的原纤维的暴露引起少突胶质细胞活力的降低。我们的结果表明，少突胶质细胞成熟和髓鞘形成在MSA脑的BCAS1阳性阶段受到损害，这可能导致缺陷少突胶质细胞的置换不足。在体外，表达BCAS1的原发少突胶质细胞对细胞外α-突触核蛋白预先形成的原纤维的高度敏感性表明，少突胶质成熟不充分参与MSA疾病进展，并支持BCAS1阳性的少突胶质细胞系细胞易于摄取的假说。体内聚集了α-突触核蛋白。这可能导致缺陷少突胶质细胞的置换不足。在体外，表达BCAS1的原发少突胶质细胞对细胞外α-突触核蛋白预先形成的原纤维的高度敏感性表明，少突胶质成熟不充分参与MSA疾病进展，并支持BCAS1阳性少突胶质细胞系细胞易于摄取的假说。体内聚集了α-突触核蛋白。这可能导致缺陷少突胶质细胞的置换不足。在体外，表达BCAS1的原发少突胶质细胞对细胞外α-突触核蛋白预先形成的原纤维的高度敏感性表明，少突胶质成熟不充分参与MSA疾病进展，并支持BCAS1阳性少突胶质细胞系细胞易于摄取的假说。体内聚集了α-突触核蛋白。