The stimulator of interferon genes (STING) pathway is upregulated in striatal astrocytes of patients with multiple system atrophy
The stimulator of interferon genes (STING) pathway is upregulated in striatal astrocytes of patients with multiple system atrophy
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DOI：
10.1016/j.neulet.2021.135972
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发表时间：
2021-05-26
影响因子：
2.5
通讯作者：
Takahashi, Ryosuke
中科院分区：
文献类型：
--
作者：
Inoue, Yutaka;Ayaki, Takashi;Takahashi, Ryosuke
多系统萎缩（MSA）是一种进行性神经退行性疾病，其特征在于致病性磷酸化α-突触核蛋白在少突胶质细胞中的积累。在受MSA影响的大脑中，也观察到严重的星形胶质细胞增生，但其在MSA发病机制中的确切作用在很大程度上仍然未知。最近，干扰素基因刺激因子（STING）通路及其下游分子I型干扰素被报道参与神经退行性变过程并在星形胶质细胞中被激活。本研究旨在研究STING通路在MSA发病机制中的作用。用于免疫组化分析的样本包括6例MSA帕金森综合征型（MSA-P），6例MSA小脑型（MSA-C）和7例年龄匹配的对照。在MSA-P病例中，在壳核和黑质中大量观察到STING和其下游分子TANK结合激酶1（TBK 1）免疫阳性的星形胶质细胞。此外，这些分子与反应性星形胶质细胞中的胶质细胞酸性蛋白（GFAP）共定位，在MSA-P患者的脑中，STING阳性星形胶质细胞的密度与GFAP阳性反应性星形胶质细胞的密度相关。这些结果表明，星形胶质细胞中STING通路相关蛋白的上调表达和随后的炎症可能有助于MSA-P的发病机制。P，为治疗MSA提供了新的治疗靶点。
Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by the accumulation of pathogenic phosphorylated alpha-synuclein in oligodendrocytes. In brains affected by MSA, severe astrogliosis is also observed, but its precise role in MSA pathogenesis remains largely unknown. Recently, the stimulator of interferon genes (STING) pathway and type I interferons, its downstream molecules, have been reported to be involved in the neurodegenerative process and to be activated in astrocytes. This study aimed to investigate the role of the STING pathway in the pathogenesis of MSA using postmortem brains. Samples used for immunohistochemical analysis included 6 cases of MSA parkinsonism type (MSA-P), 6 cases of MSA cerebellar type (MSA-C), and 7 age-matched controls. In MSA-P cases, astrocytes immunopositive for STING and TANK-binding kinase 1 (TBK1), its downstream molecule, were abundantly observed in the putamen and the substantia nigra. Moreover, these molecules colocalized with glial fibrillary acidic protein (GFAP) in reactive astrocytes, and the density of STING-positive astrocytes correlated with that of GFAP-positive reactive astrocytes in the brains of patients with MSA-P. These results suggest that the upregulated expression of STING pathway-related proteins in astrocytes and the subsequent inflammation may contribute to the pathogenesis in MSA-P and could provide novel therapeutic targets for the treatment of MSA.