Nocardia asteroides-Induced movement abnormalities in mice: Relevance for Parkinson's disease?
Nocardia asteroides-Induced movement abnormalities in mice: Relevance for Parkinson's disease?
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DOI：
10.1002/mds.26711
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发表时间：
2016-08
期刊：
影响因子：
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通讯作者：
Camp DM
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文献类型：
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作者：
Loeffler DA;LeWitt PA;Camp DM
在大多数帕金森氏病(PD)病例中，缺乏遗传原因的证据，1因此寻求了替代的解释。2、3由于这种疾病最早是在2个世纪前被描述的，它不可能是由现代化学物质或饮食暴露引起的。流行病学研究表明，大多数帕金森病病例可能是基因和环境因素相互作用的结果。2脑后帕金森综合征的流行样蔓延提示帕金森病可能是感染性因素所致。4对这一假设的额外支持来自病毒性脑炎的病例，其中已发展为帕金森症5，以及关于夫妻帕金森症的报道6(这可能是常见环境暴露的结果)。1991年。加州大学戴维斯分校的Shunro Kohbata博士和Blaine Beaman博士描述了在Bagg Albino/c(BALB/c)小鼠身上出现的运动异常，他们感染了一种革兰氏阳性抗酸细菌，名为诺卡氏菌星状诺卡氏菌，乔治敦大学医院2(GUH-2)7(后来更名为N.cyriacigorgica)。随后，我们与毕曼博士合作，进一步研究了这一模型。这个观点回顾了我们和Beaman博士的发现，并阐述了这一模型与帕金森病的相关性。Kohbata和Beaman描述的模型与PD有一些有趣的临床和神经病理学相似之处。动物出现运动异常(尾部悬吊时旋转[以下称为尾部旋转])、摇头、运动减慢和尾部定位时弯曲的轴向姿势)、黑质纹状体多巴胺丢失和路易体样神经元内包涵体(图1)。随附的视频显示了这些运动异常(参见辅助信息)。服用左旋多巴或卡比多巴可使摇头停止长达2小时。7夹杂物呈圆形或椭圆形。苏木精-伊红染色产生苏木精染色的内核和伊红染色的外部结构。神经化学研究发现，尽管运动异常持续存在，纹状体多巴胺(DA)在感染后第29天下降了72%，8在感染后1年恢复到对照水平。感染后第7天、第16天或第29天纹状体5-羟色胺或去甲肾上腺素未见变化。我们调查了诺卡氏菌是否分泌了一种多巴胺耗竭毒素。我们将大鼠嗜铬细胞瘤PC12细胞与GUH-2菌株无菌培养滤液孵育24小时，发现细胞内DA水平下降了65%，在此期间细胞活力损失最小(在以后的时间点确实有所下降)。在后来的研究中，我们将这一点本地化
Evidence for genetic causes is lacking in most Parkinson’s disease (PD) cases, 1 so alternative explanations have been sought. 2, 3 Because the disease was first described 2 centuries ago, it cannot be caused by modern chemical or dietary exposures. Epidemiological studies suggest that most cases of PD may be a result of interactions of genes and environmental factors. 2 The possibility that PD might be a result of an infectious agent was suggested by the epidemic-like spreading of postencephalitic parkinsonism. 4 Additional support for this hypothesis comes from cases of viral encephalitis in which parkinsonism has developed5 and reports of conjugal parkinsonism6 (which could be a result of common environmental exposure). In 1991. Drs. Shunro Kohbata and Blaine Beaman from the University of California at Davis described motor abnormalities that developed in Bagg Albino/c (BALB/c) mice that they infected with a Gram-positive, acid-fast bacterium named Nocardia asteroides strain Georgetown University Hospital 2 (GUH-2) 7 (since renamed N. cyriacigeorgica.). We subsequently collaborated with Dr. Beaman to investigate this model further. This viewpoint reviews our findings and those of Dr. Beaman and addresses the relevance of this model for PD. The model described by Kohbata and Beaman had some interesting clinical and neuropathological similarities to PD. The animals developed movement abnormalities (spinning when suspended by the tail [referred to hereafter as “tail spinning”], head shaking, slowed movements, and flexed axial posture with tail positioning), nigrostriatal dopamine loss, and Lewy body–like intraneuronal inclusions (Fig. 1). The accompanying video shows these movement abnormalities (see supporting information). The head shaking could be stopped for up to 2 hours by administration of levodopa or carbidopa. 7 The inclusions were circular or oval shaped. Hematoxylin and eosin staining produced a hematoxylin-stained inner core and eosin-stained outer structure. Neurochemical studies found striatal dopamine (DA) to be decreased by 72% on day 29, 8 returning to control levels by 1 year postinfection despite persistence of the movement abnormalities. No changes in striatal serotonin or norepinephrine were found on postinfection days 7, 16, or 29. We investigated whether Nocardia secreted a dopamine-depleting toxin. We incubated rat pheochromocytoma PC12 cells with strain GUH-2 sterile culture filtrate for 24 hours and found a 65% decrease in intracellular DA levels, at which time there was minimal loss of cell viability9 (which did decrease at later time points). In a later study, we localized this