Sustained expression of PGC-1α in the rat nigrostriatal system selectively impairs dopaminergic function.
Sustained expression of PGC-1α in the rat nigrostriatal system selectively impairs dopaminergic function.
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DOI：
10.1093/hmg/ddr618
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发表时间：
2012-04-15
影响因子：
3.5
通讯作者：
Schneider BL
中科院分区：
文献类型：
--
作者：
Ciron C;Lengacher S;Dusonchet J;Aebischer P;Schneider BL
线粒体功能障碍和氧化应激与帕金森病的病因有关。因此，控制线粒体活性的途径迅速成为潜在的治疗靶点。在这里，我们探讨了神经元对过氧化物酶体增殖物激活受体γ共激活因子-1 α（PGC-1α）长期过表达的反应，PGC-1 α是一种线粒体功能的转录调节因子，在体外和体内。在来自腹侧中脑的神经元原代培养物中，PGC-1α诱导线粒体生物合成并增加基础呼吸。随着时间的推移，我们观察到用于产生三磷酸腺苷的神经元消耗的氧气比例增加。与氧化磷酸化增强平行，PGC-1α逐渐导致线粒体极化降低。在成年大鼠黑质纹状体系统，腺相关病毒（AAV）介导的PGC-1α过表达诱导多巴胺能标记物的选择性丢失，并增加多巴胺（DA）的catalysts，导致纹状体DA含量减少。此外，PGC-1α阻止纹状体注射荧光金逆行示踪剂后黑质神经元的标记。当PGC-1α在黑质内注射AAV后以更高水平表达时，它导致多巴胺能神经元的明显变性。最后，PGC-1α过表达不能阻止由α-突触核蛋白过表达诱导的病理条件下的黑质纹状体变性。总之，我们发现PGC-1α的持续过表达导致神经元细胞代谢活性的重大改变，从而显著损害体内多巴胺能功能。这些结果强调了PGC-1α在多巴胺能神经元的功能和存活中的核心作用，以及维持PGC-1α活性的生理水平的迫切需要。
Mitochondrial dysfunction and oxidative stress have been implicated in the etiology of Parkinson's disease. Therefore, pathways controlling mitochondrial activity rapidly emerge as potential therapeutic targets. Here, we explore the neuronal response to prolonged overexpression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), a transcriptional regulator of mitochondrial function, both in vitro and in vivo. In neuronal primary cultures from the ventral midbrain, PGC-1α induces mitochondrial biogenesis and increases basal respiration. Over time, we observe an increasing proportion of the oxygen consumed by neurons which are dedicated to adenosine triphosphate production. In parallel to enhanced oxidative phosphorylation, PGC-1α progressively leads to a decrease in mitochondrial polarization. In the adult rat nigrostriatal system, adeno-associated virus (AAV)-mediated overexpression of PGC-1α induces the selective loss of dopaminergic markers and increases dopamine (DA) catabolism, leading to a reduction in striatal DA content. In addition, PGC-1α prevents the labeling of nigral neurons following striatal injection of the fluorogold retrograde tracer. When PGC-1α is expressed at higher levels following intranigral AAV injection, it leads to overt degeneration of dopaminergic neurons. Finally, PGC-1α overexpression does not prevent nigrostriatal degeneration in pathologic conditions induced by α-synuclein overexpression. Overall, we find that lasting overexpression of PGC-1α leads to major alterations in the metabolic activity of neuronal cells which dramatically impair dopaminergic function in vivo. These results highlight the central role of PGC-1α in the function and survival of dopaminergic neurons and the critical need for maintaining physiological levels of PGC-1α activity.
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