α-Synuclein expression and Nrf2 deficiency cooperate to aggravate protein aggregation, neuronal death and inflammation in early-stage Parkinson's disease
α-Synuclein expression and Nrf2 deficiency cooperate to aggravate protein aggregation, neuronal death and inflammation in early-stage Parkinson's disease
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DOI：
10.1093/hmg/dds143
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发表时间：
2012-07-15
影响因子：
3.5
通讯作者：
Cuadrado, Antonio
中科院分区：
文献类型：
--
作者：
Lastres-Becker, Isabel;Ulusoy, Ayse;Cuadrado, Antonio
虽然-突触核蛋白（-SYN）聚集是散发性和家族性帕金森病（PD）的标志，但尚不清楚它如何促成PD发病机制的早期事件，如氧化和炎症应激。在这里，我们在一种新的动物模型中解决了这个问题，该模型基于腺相关病毒载体（rAAV）的立体定位递送，用于在缺乏转录因子Nrf 2（Nrf 2（/））的小鼠的腹侧中脑中表达人-SYN。手术后两个月，Nrf 2（/）小鼠表现出黑质多巴胺能神经元变性加重，营养不良树突增加，令人想起Lewy神经突，这与蛋白酶体基因表达和活性受损有关。多巴胺能神经元丢失与Nrf 2（/）小鼠中神经炎症和神经胶质增生的增加有关。作为对外源性-SYN的反应，Nrf 2（/）小胶质细胞不能激活两种抗炎基因血红素加氧酶-1（HO-1）和烟酰胺腺嘌呤二核苷酸磷酸醌氧化还原酶-1（NQO 1）的表达。这种受损的Nrf 2反应与小胶质细胞活化谱的转变相关，朝向促炎标志物IL-6、IL-1和iNOS的产生增加和荧光珠的吞噬能力降低以及TAM受体Axl和Mer的信使RNA水平降低。PD早期至中期进展患者的尸检脑组织样本显示星形胶质细胞和小胶质细胞中HO-1表达增加，表明患病大脑试图通过激活Nrf 2通路来补偿PD的这些标志。这项研究表明，-SYN和Nrf 2缺陷合作蛋白聚集，神经炎症和神经元死亡，并提供了一个双因素的动物模型，以研究早期PD。
Although -synuclein (-SYN) aggregation is a hallmark of sporadic and familial Parkinsons disease (PD), it is not known how it contributes to early events of PD pathogenesis such as oxidative and inflammatory stress. Here, we addressed this question in a new animal model based on stereotaxic delivery of an adeno-associated viral vector (rAAV) for expression of human -SYN in the ventral midbrain of mice lacking the transcription factor Nrf2 (Nrf2(/)). Two months after surgery, Nrf2(/) mice exhibited exacerbated degeneration of nigral dopaminergic neurons and increased dystrophic dendrites, reminiscent of Lewy neurites, which correlated with impaired proteasome gene expression and activity. Dopaminergic neuron loss was associated with an increase in neuroinflammation and gliosis that were intensified in Nrf2(/) mice. In response to exogenously added -SYN, Nrf2(/) microglia failed to activate the expression of two anti-inflammatory genes, heme oxygenase-1 (HO-1) and nicotinamide adenine dinucleotide phosphate quinone oxidorreductase-1 (NQO1). This impaired Nrf2 response correlated with a shift in the microglial activation profile, towards increased production of proinflammatory markers, IL-6, IL-1 and iNOS and reduced phagocytic capacity of fluorescent beads, and lower messenger RNA levels for TAM receptors Axl and Mer. Postmortem brain tissue samples from patients in early- to middle-stage progression of PD showed increased HO-1 expression in astrocytes and microglia, suggesting an attempt of the diseased brain to compensate these hallmarks of PD through activation of the Nrf2 pathway. This study demonstrates that -SYN and Nrf2 deficiency cooperate on protein aggregation, neuroinflammation and neuronal death and provides a bifactorial animal model to study early-stage PD.