Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Brain Pathol. 2019 May;29(3):380-396. doi: 10.1111/bpa.12678. Epub 2019 Jan 31.
Neuroinflammation and oligodendroglial cytoplasmic α-synuclein (α-syn) inclusions (GCIs) are important neuropathological characteristics of multiple system atrophy (MSA). GCIs are known to interfere with oligodendroglial maturation and consequently result in myelin loss. The neuroinflammatory phenotype in the context of MSA, however, remains poorly understood. Here, we demonstrate MSA-associated neuroinflammation being restricted to myeloid cells and tightly linked to oligodendroglial α-syncleinopathy. In human putaminal post-mortem tissue of MSA patients, neuroinflammation was observed in white matter regions only. This locally restricted neuroinflammation coincided with elevated numbers of α-syn inclusions, while gray matter with less α-synucleinopathy remained unaffected. In order to analyze the temporal pattern of neuroinflammation, a transgenic mouse model overexpressing human α-syn under the control of an oligodendrocyte-specific myelin basic protein (MBP) promoter (MBP29-hα-syn mice) was assessed in a pre-symptomatic and symptomatic disease stage. Strikingly, we detected an increased neuroinflammation in regions with a high α-syn load, the corpus callosum and the striatum, of MBP29-hα-syn mice, already at a pre-symptomatic stage. Furthermore, this inflammatory response was restricted to myeloid cells being highly proliferative and showing an activated, phagocytic phenotype. In contrast, severe astrogliosis was observed only in gray matter regions of MSA patients as well as MBP29-hα-syn mice. To further characterize the influence of oligodendrocytes on initiation of the myeloid immune response, we performed RNA sequencing analysis of α-syn overexpressing primary oligodendrocytes. A distinct gene expression profile including upregulation of cytokines important for myeloid cell attraction and proliferation was detected in α-syn overexpressing oligodendrocytes. Additionally, microdissected tissue of MBP29-hα-syn mice exhibited a similar cellular gene expression profile in white matter regions even pre-symptomatically. Collectively, these results imply an early crosstalk between neuroinflammation and oligodendrocytes containing α-syn inclusions leading to an immune response locally restricted to white matter regions in MSA.
神经炎症和少突胶质细胞细胞质α-突触核蛋白（α-syn）包含物（GCIs）是多系统萎缩（MSA）的重要神经病理学特征。已知 GCIs 干扰少突胶质细胞成熟，从而导致髓鞘丢失。然而，MSA 背景下的神经炎症表型仍知之甚少。在这里，我们证明 MSA 相关的神经炎症仅限于髓样细胞，并与少突胶质细胞α-syn 病理学紧密相关。在 MSA 患者的纹状体死后组织中，仅在白质区域观察到神经炎症。这种局部受限的神经炎症与 α-syn 包含物的数量增加相一致，而少突胶质细胞α-syn 病变较少的灰质不受影响。为了分析神经炎症的时间模式，评估了在一个预先存在的和有症状的疾病阶段，在一个过表达人α-syn 的转基因小鼠模型下，其表达受少突胶质细胞特异性髓鞘碱性蛋白（MBP）启动子（MBP29-hα-syn 小鼠）的控制。令人惊讶的是，我们在 MBP29-hα-syn 小鼠的胼胝体和纹状体等具有高α-syn 负荷的区域中检测到神经炎症的增加，甚至在预先存在的症状阶段。此外，这种炎症反应仅限于高度增殖并表现出激活、吞噬表型的髓样细胞。相比之下，严重的星形胶质增生仅在 MSA 患者以及 MBP29-hα-syn 小鼠的灰质区域中观察到。为了进一步描述少突胶质细胞对髓样免疫反应启动的影响，我们对过表达α-syn 的原代少突胶质细胞进行了 RNA 测序分析。在过表达α-syn 的少突胶质细胞中，检测到一个独特的基因表达谱，包括上调对髓样细胞吸引和增殖很重要的细胞因子。此外，即使在预先存在症状的情况下，MBP29-hα-syn 小鼠的微分离组织也在白质区域表现出相似的细胞基因表达谱。总的来说，这些结果表明，神经炎症和包含 α-syn 包含物的少突胶质细胞之间存在早期相互作用，导致 MSA 中局限于白质区域的免疫反应。
