Accumulation of mitochondrial DNA deletions within dopaminergic neurons triggers neuroprotective mechanisms
Accumulation of mitochondrial DNA deletions within dopaminergic neurons triggers neuroprotective mechanisms
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DOI：
10.1093/brain/awt196
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发表时间：
2013-08-01
期刊：
影响因子：
14.5
通讯作者：
Vila, Miquel
中科院分区：
文献类型：
--
作者：
Perier, Celine;Bender, Andreas;Vila, Miquel
线粒体DNA的获得性改变被认为在帕金森病中起致病作用。特别是，在帕金森病患者和老年人的黑质多巴胺能神经元中观察到线粒体DNA缺失的积累。此外，线粒体DNA聚合酶γ的突变导致多个线粒体DNA缺失，这可能与左旋多巴反应性帕金森病和严重的黑质多巴胺能神经变性有关。然而，线粒体DNA缺失是否在多巴胺能神经元的死亡中发挥了致病作用仍不清楚。在这里，我们评估了潜在的致病作用的线粒体DNA缺失的多巴胺能黑质纹状体系统，通过使用突变小鼠拥有校对缺陷形式的线粒体DNA聚合酶γ（POLG（D257 A）），这导致在一个时间依赖性积累的线粒体DNA缺失的几个组织，包括大脑。在这些动物中，我们评估的发生个别黑质多巴胺能神经元内的线粒体DNA缺失，激光捕获显微切割和定量实时聚合酶链反应，并确定了潜在的有害影响，线粒体功能和多巴胺能神经元的完整性，细胞色素c氧化酶组织化学和定量形态学的线粒体DNA的改变。来自POLG（D257 A）小鼠的黑质多巴胺能神经元积累线粒体DNA缺失至与帕金森病患者和老年个体相似的程度（类似于40-60%）。尽管如此高水平的线粒体DNA缺失，这些动物的黑质多巴胺能神经元的大部分没有表现出线粒体功能障碍或变性。只有少数个体黑质丘脑部神经元表现为细胞色素c氧化酶阴性，其表现出比细胞色素c氧化酶阳性细胞更高水平的线粒体DNA缺失（60.38 +/- 3.92%对45.18 +/- 2.83%）。POLG（D257 A）小鼠多巴胺能神经元的存活与线粒体DNA拷贝数增加、线粒体嵴网络增强、线粒体呼吸改善、纹状体源性活性氧加重减少、纹状体多巴胺水平升高和对帕金森病线粒体神经毒素的抵抗有关。这些结果表明，黑质多巴胺能神经元内线粒体DNA缺失的主要积累，在帕金森病患者中观察到的程度相似，不杀死多巴胺能神经元，但在线粒体水平上触发神经保护性代偿机制，这可能是这些细胞中线粒体DNA缺失的高致病阈值的原因。
Acquired alterations in mitochondrial DNA are believed to play a pathogenic role in Parkinson's disease. In particular, accumulation of mitochondrial DNA deletions has been observed in substantia nigra pars compacta dopaminergic neurons from patients with Parkinson's disease and aged individuals. Also, mutations in mitochondrial DNA polymerase gamma result in multiple mitochondrial DNA deletions that can be associated with levodopa-responsive parkinsonism and severe substantia nigra pars compacta dopaminergic neurodegeneration. However, whether mitochondrial DNA deletions play a causative role in the demise of dopaminergic neurons remains unknown. Here we assessed the potential pathogenic effects of mitochondrial DNA deletions on the dopaminergic nigrostriatal system by using mutant mice possessing a proofreading-deficient form of mitochondrial DNA polymerase gamma (POLG(D257A)), which results in a time-dependent accumulation of mitochondrial DNA deletions in several tissues, including the brain. In these animals, we assessed the occurrence of mitochondrial DNA deletions within individual substantia nigra pars compacta dopaminergic neurons, by laser capture microdissection and quantitative real-time polymerase chain reaction, and determined the potential deleterious effects of such mitochondrial DNA alterations on mitochondrial function and dopaminergic neuronal integrity, by cytochrome c oxidase histochemistry and quantitative morphology. Nigral dopaminergic neurons from POLG(D257A) mice accumulate mitochondrial DNA deletions to a similar extent (similar to 40-60%) as patients with Parkinson's disease and aged individuals. Despite such high levels of mitochondrial DNA deletions, the majority of substantia nigra pars compacta dopaminergic neurons from these animals did not exhibit mitochondrial dysfunction or degeneration. Only a few individual substantia nigra pars compacta neurons appeared as cytochrome c oxidase-negative, which exhibited higher levels of mitochondrial DNA deletions than cytochrome c oxidase-positive cells (60.38 +/- 3.92% versus 45.18 +/- 2.83%). Survival of dopaminergic neurons in POLG(D257A) mice was associated with increased mitochondrial DNA copy number, enhanced mitochondrial cristae network, improved mitochondrial respiration, decreased exacerbation of mitochondria-derived reactive oxygen species, greater striatal dopamine levels and resistance to parkinsonian mitochondrial neurotoxins. These results indicate that primary accumulation of mitochondrial DNA deletions within substantia nigra pars compacta dopaminergic neurons, at an extent similar to that observed in patients with Parkinson's disease, do not kill dopaminergic neurons but trigger neuroprotective compensatory mechanisms at a mitochondrial level that may account for the high pathogenic threshold of mitochondrial DNA deletions in these cells.