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首页> 外文期刊>Journal of neuroinflammation >Analysis of inflammation-related nigral degeneration and locomotor function in DJ-1?/? mice
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Analysis of inflammation-related nigral degeneration and locomotor function in DJ-1?/? mice

机译：DJ-1 ？/？小鼠炎症相关的黑色素变性和运动功能分析

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Background Complex interactions involving genetic susceptibility and environmental factors are thought to underlie the pathogenesis of Parkinson’s disease (PD). Although the role of inflammatory processes in modulating risk for development of PD has yet to be fully understood, prospective studies suggest that chronic use of NSAIDs reduce the incidence of PD. Loss-of-function mutations in the DJ-1 gene cause a rare form of familial PD with an autosomal recessive pattern of inheritance; however, DJ-1?/? mice do not display nigrostriatal pathway degeneration, suggesting that additional factors such as inflammation may be needed to induce neurodegeneration on the background of DJ-1 gene mutations. Neuroinflammation causes oxidative stress and, based on evidence that DJ-1 plays a protective role against oxidative stress, we investigated whether DJ-1?/? mice display increased vulnerability to inflammation-induced nigral degeneration. Methods We exposed adult wild-type and DJ-1?/? mice to repeated intranasal administration of soluble TNF (inTNF) or repeated intraperitoneal injections of low-dose lipopolysaccharide (LPS) or saline vehicle. We measured locomotor performance using a variety of behavior tasks, striatal dopamine (DA) content by HPLC, DA neuron (TH+ cells) and total neuron (NeuN+ cells) number in the substantia nigra pars compacta and ventral tegmental area by unbiased stereology, number of Iba1-positive microglia, and mRNA levels of inflammatory and oxidative stress genes by quantitative PCR in the midbrain, cortex and isolated peritoneal macrophages of DJ-1?/? and wild-type mice. Results We found that chronic LPS injections induced similar neuroinflammatory responses in the midbrains of DJ-1?/? mice and wild-type mice and neither group developed locomotor deficits or nigral degeneration. inTNF administration did not appear to induce neuroinflammatory responses in LPS-treated wild-type or DJ-1?/? mice. The lack of vulnerability to inflammation-induced nigral degeneration was not due to enhanced anti-oxidant gene responses in the midbrains of DJ-1?/? mice which, in fact, displayed a blunted response relative to that of wild-type mice. Peripheral macrophages from wild-type and DJ-1?/? mice displayed similar basal and LPS-induced inflammatory and oxidative stress markers in vitro. Conclusions Our studies indicate that DJ-1?/? mice do not display increased vulnerability to inflammation-related nigral degeneration in contrast to what has been reported for 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine. We conclude that either DJ-1 does not have a critical role in protecting DA neurons against inflammation-induced oxidative stress and/or there is compensatory gene expression in the midbrain of DJ-1?/? mice that renders them resistant to the cytotoxic effects triggered by chronic peripheral inflammation.
机译：背景技术涉及遗传易感性和环境因素的复杂相互作用被认为是帕金森氏病（PD）发病机理的基础。尽管炎症过程在调节PD发生风险中的作用尚未完全了解，但前瞻性研究表明，长期使用NSAIDs可以降低PD的发生率。 DJ-1基因的功能丧失突变导致罕见的家族性PD，具有常染色体隐性遗传。但是DJ-1？/？小鼠没有表现出黑质纹状体途径变性，提示可能需要其他因素（例如炎症）来诱导DJ-1基因突变为背景的神经变性。神经炎症会引起氧化应激，并根据DJ-1对氧化应激起保护作用的证据，我们调查了DJ-1β/β是否存在。小鼠表现出更高的抵抗炎症性黑质变性的能力。方法我们暴露了成年野生型和DJ-1？/?。小鼠反复鼻内施用可溶性TNF（inTNF）或反复腹膜内注射低剂量脂多糖（LPS）或生理盐水。我们使用各种行为任务，通过HPLC的纹状体多巴胺（DA）含量，黑质致密部黑质和腹侧被盖区中无偏见的立体视觉的DA神经元（TH +细胞）和总神经元（NeuN +细胞）数量来测量运动能力。定量PCR检测DJ-1β/β中脑，皮层和腹膜巨噬细胞中Iba1阳性小胶质细胞和炎症和氧化应激基因的mRNA水平。和野生型小鼠。结果我们发现，慢性LPS注射在DJ-1β/β的中脑中引起了类似的神经炎症反应。小鼠和野生型小鼠，两组均未出现运动功能障碍或黑色素变性。在LPS处理的野生型或DJ-1α/β中，TNFα的注射似乎没有诱导神经炎症反应。老鼠。缺乏对炎症性黑质变性的抵抗力，并不是由于DJ-1β/β中脑的抗氧化基因反应增强。实际上，与野生型小鼠相比，它们的反应迟钝。来自野生型和DJ-1α/β的外周巨噬细胞小鼠在体外显示出相似的基础和LPS诱导的炎症和氧化应激标记。结论我们的研究表明DJ-1？/?。与已报道的1-甲基-4-苯基-1,2,3,6-四氢吡喃啶相反，小鼠对炎症相关的黑质变性的脆弱性没有增加。我们得出结论，DJ-1在保护DA神经元免受炎症诱导的氧化应激和/或DJ-1β/β中脑中存在补偿性基因表达方面没有关键作用。使它们对慢性外周炎症引发的细胞毒性作用具有抗性的小鼠。

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