帕金和PINK1可以缓解由STING引起的炎症
Danielle A Sliter1, Jennifer Martinez2, Ling Hao1
1Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
Nature
|August 24, 2018
概括
帕金森病的PINK1和parkin基因通常清除受损的线粒体. 它们的缺失会导致炎症和神经元损失, 通过阻断STING来预防,
科学领域:
- 神经科学
- 免疫学
- 细胞生物学
背景情况:
- 帕金森病 (PD) 与增高的促炎细胞因子有关,但炎症在神经退行症中的作用尚不清楚.
- 帕金基因 (PRKN) 和PINK1的突变导致早期发病的PD,并且参与了线粒体消化,这是去除受损线粒体的途径.
- 人们对 mitophagy 的 in vivo 功能及其与炎症的联系仍然不太了解,部分原因是淘汰小鼠缺乏相关的表型.
研究的目的:
- 在体内研究PINK1和parkin在调节先天免疫和炎症中的作用.
- 通过PINK1和parkin调节的线粒细胞衰变是否抑制炎症反应.
- 在帕金森病模型中探索炎症,菌体缺陷和神经退行之间的联系.
主要方法:
- 产生和分析Prkn-/-和Pink1-/-小鼠,包括具有线粒体DNA突变的Prkn-/-;突变小鼠.
- 通过大量运动和线粒体DNA突变诱导炎症表型.
- 通过遗传删除STING (干扰素基因刺激剂) 来评估炎症反应和救援.
- 在老年Prkn-/;突变小鼠中评估多巴胺基神经元损失和运动缺陷以及STING删除的影响.
主要成果:
- 在耗尽性运动后或在线粒体DNA突变的存在下,Prkn-/和Pink1-/小鼠表现出显著的炎症表型.
- 在没有STING的小鼠中,运动或线粒体DNA损伤引起的炎症完全消失.
- 失去了STING也挽救了多巴胺基神经元的损失和老年Prkn-/-;突变小鼠的运动缺陷,这表明了炎症在这些PD相关的表型中的作用.
- 在患有PRKN突变的人群中观察到细胞因子升高.
结论:
- PINK1和parkin通过菌作用在抑制先天免疫反应方面发挥着至关重要的作用.
- 由STING调节的线粒体功能障碍和随后的炎症,在帕金森病模型中导致神经退行.
- 这些发现突显了线粒体质量控制,炎症和帕金森病的发病之间的关键联系.
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