Pgc-1α overexpression downregulates Pitx3 and increases susceptibility to MPTP toxicity associated with decreased Bdnf.
Pgc-1α overexpression downregulates Pitx3 and increases susceptibility to MPTP toxicity associated with decreased Bdnf.
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DOI：
10.1371/journal.pone.0048925
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Simon DK
中科院分区：
文献类型：
--
作者：
Clark J;Silvaggi JM;Kiselak T;Zheng K;Clore EL;Dai Y;Bass CE;Simon DK
多种机制可能导致帕金森病（PD）中的神经元死亡，包括线粒体功能障碍和氧化应激。过氧化物酶体增殖物激活受体γ共激活因子-1 α（PGC-1α）积极调节线粒体生物合成和细胞抗氧化反应所需基因的表达。此外，PGC-1α调节基因在PD早期黑质（SN）神经元中的表达较低。因此，上调PGC-1α是PD中的候选神经保护策略。在此，使用腺相关病毒（AAV）诱导野生型C57 BL/6CR小鼠SN中Pgc-1α或对照基因的单侧过表达。在施用AAV后三周，用盐水或MPTP处理小鼠。SN中Pgc-1α的过表达诱导靶基因的表达，但出乎意料的是，它也大大降低了酪氨酸羟化酶（Th）和多巴胺能表型的其他标志物的表达，导致纹状体多巴胺的严重损失。Th表达减少与Pitx 3的丢失有关，Pitx 3是一种对多巴胺能细胞的发育和维持至关重要的转录因子。同样受Pitx 3调控的神经营养因子Bdnf的表达也减少了。Pgc-1α的过表达还导致Th+神经元对MPTP诱导的死亡的敏感性增加。在没有MPTP处理的情况下，单独的Pgc-1α过表达不会导致SN中的细胞损失或多巴胺能末梢的损失。这些数据表明，Pgc-1α的过表达导致与较低水平的Pitx 3相关的多巴胺耗竭，并增强对MPTP的易感性。这些数据可能对靶向PD中PGC-1α过表达的神经保护策略产生影响。
Multiple mechanisms likely contribute to neuronal death in Parkinson’s disease (PD), including mitochondrial dysfunction and oxidative stress. Peroxisome proliferator-activated receptor gamma co-activator-1 alpha (PGC-1α) positively regulates the expression of genes required for mitochondrial biogenesis and the cell’s antioxidant responses. Also, expression of PGC-1α-regulated genes is low in substantia nigra (SN) neurons in early PD. Thus upregulation of PGC-1α is a candidate neuroprotective strategy in PD. Here, an adeno-associated virus (AAV) was used to induce unilateral overexpression of Pgc-1α, or a control gene, in the SN of wild-type C57BL/6CR mice. Three weeks after AAV administration, mice were treated with saline or MPTP. Overexpression of Pgc-1α in the SN induced expression of target genes, but unexpectedly it also greatly reduced the expression of tyrosine hydroxylase (Th) and other markers of the dopaminergic phenotype with resultant severe loss of striatal dopamine. Reduced Th expression was associated with loss of Pitx3, a transcription factor that is critical for the development and maintenance of dopaminergic cells. Expression of the neurotrophic factor Bdnf, which also is regulated by Pitx3, similarly was reduced. Overexpression of Pgc-1α also led to increased sensitivity to MPTP-induced death of Th+ neurons. Pgc-1α overexpression alone, in the absence of MPTP treatment, did not lead to cell loss in the SN or to loss of dopaminergic terminals. These data demonstrate that overexpression of Pgc-1α results in dopamine depletion associated with lower levels of Pitx3 and enhances susceptibility to MPTP. These data may have ramifications for neuroprotective strategies targeting overexpression of PGC-1α in PD.