Mitochondrial dysfunction and altered ribostasis in hippocampal neurons with cytoplasmic inclusions of multiple system atrophy
Mitochondrial dysfunction and altered ribostasis in hippocampal neurons with cytoplasmic inclusions of multiple system atrophy
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DOI：
10.1111/neup.12482
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发表时间：
2018-08-01
期刊：
影响因子：
2.3
通讯作者：
Iwaki, Toru
中科院分区：
文献类型：
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作者：
Maeda, Norihisa;Honda, Hiroyuki;Iwaki, Toru
多系统萎缩(MSA)是一种散发性成人起病的神经退行性疾病。最近的研究表明，伴有认知功能减退的MSA患者边缘神经元内可见大量神经元胞浆内包涵体(NCIS)。我们通过分析12例经病理证实的MSA，通过确定线粒体功能和RNA处理状态，研究了这些NCI形成的潜在机制。其中4例接受了认知功能障碍的半定量评估，免疫组织化学分析显示，与无认知功能障碍的患者相比，有认知功能障碍的患者在海马CA1区、下丘脑和杏仁核的NCI负荷明显增加。免疫荧光染色显示，患有NCIS的边缘神经元经常加速活性氧(ROS)的产生，并降低线粒体的质量控制。免疫荧光染色还显示，具有这些NCI的神经元将异质性核核糖核蛋白A1(HNRNPA1)从细胞核移位，并异常聚集在核周边缘。由于认知损害的MSA大鼠海马神经元中NCI数目较多，NCI结构中神经元线粒体功能障碍和核糖体沉积改变可能参与了MSA大鼠海马区的退行性变。
Multiple system atrophy (MSA) is a sporadic adult-onset neurodegenerative disease. It has recently been shown that patients with MSA accompanied by cognitive decline display numerous neuronal cytoplasmic inclusions (NCIs) in the limbic neurons. We examined potential mechanisms underlying the formation of these NCIs by determining of mitochondrial function and statuses of RNA processing by analyzing 12 pathologically confirmed cases of MSA. Among them, four had cognitive impairment Semiquantitative evaluation using immunohistochemistry analyses revealed a significantly greater NCI burden in the hippocampal cornu ammonis 1 (CA1) subfield, subiculum, and amygdala in the cases with cognitive impairments compared with those without cognitive impairment. Immunofluorescent staining revealed that limbic neurons with NCIs often accelerated production of reactive oxygen species (ROS) and degraded mitochondrial quality control. Immunofluorescent staining also revealed that neurons with these NCIs translocated heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) from the nucleus and aggregated abnormally at the perinuclear rim. Since the NCIs in the hippocampal neurons of MSA with cognitive impairments were more numerous, the neuronal mitochondrial dysfunction and altered ribostasis observed in NCI formation may be involved in the hippocampal degeneration of MSA.