Inactivation of Drosophila DJ-1 leads to impairments of oxidative stress response and phosphatidylinositol 3-kinase/Akt signaling
Inactivation of Drosophila DJ-1 leads to impairments of oxidative stress response and phosphatidylinositol 3-kinase/Akt signaling
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DOI：
10.1073/pnas.0504610102
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发表时间：
2005-09-20
影响因子：
11.1
通讯作者：
Lu, BW
中科院分区：
文献类型：
--
作者：
Yang, YF;Gehrke, S;Lu, BW
帕金森病（Parkinson's disease，PD）是最常见的以多巴胺能神经元功能障碍和退行性变为特征的运动障碍。大多数PD病例的原因尚不清楚，尽管尸检研究表明与氧化应激有关。家族性PD相关基因的鉴定为研究模型生物中PD发病机制提供了机会。在这里，我们表明，DJ-1A，果蝇同源的家族PD相关基因DJ-1，在氧化应激反应和神经元的维护中起着至关重要的作用。通过RNA干扰（RNAi）抑制DJ-1A功能导致活性氧物质的细胞积累、生物体对氧化应激的超敏反应以及多巴胺能和感光神经元的功能障碍和变性。为了鉴定可能与DJ-1A在调节细胞存活中相互作用的其他基因，我们进行了遗传相互作用研究，并鉴定了磷脂酰肌醇3-激酶（PI 3 K）/Akt信号通路的组分作为DJ-1A RNAi诱导的神经变性的特异性调节剂。PI 3 K信号转导至少部分通过降低细胞活性氧水平来抑制DJ-1A RNAi表型。与遗传相互作用的结果一致，我们还发现DJ-1A RNAi动物中Akt的磷酸化减少，表明DJ-1A下调对PI 3 K/Akt信号传导的损害，连同最近在哺乳动物系统中的发现，这些结果暗示DJ-1相关疾病发病机制中PI 3 K/Akt信号传导和氧化应激反应的损害。我们还观察到PD的果蝇parkin模型中PI 3 K/Akt信号传导的损伤，暗示PD发病机制中的常见分子事件。因此，PI 3 K/Akt信号转导的操纵可以为PD的治疗提供治疗益处。
Parkinson's disease (PD) is the most common movement disorder characterized by dopaminergic dysfunction and degeneration. The cause of most PD cases is unknown, although postmortem studies have implicated the involvement of oxidative stress. The identification of familial PD-associated genes offers the opportunity to study mechanisms of PD pathogenesis in model organisms. Here, we show that DJ-1A, a Drosophila homologue of the familial PD-associated gene DJ-1, plays an essential role in oxidative stress response and neuronal maintenance. Inhibition of DJ-1A function through RNA interference (RNAi) results in cellular accumulation of reactive oxygen species, organismal hypersensitivity to oxidative stress, and dysfunction and degeneration of dopaminergic and photoreceptor neurons. To identify other genes that may interact with DJ-1A in regulating cell survival, we performed genetic interaction studies and identified components of the phosphatidylinositol 3-kinase (PI3K)/Akt-signaling pathway as specific modulators of DJ-1A RNAi-induced neurodegeneration. PI3K signaling suppresses DJ-1A RNAi phenotypes at least in part by reducing cellular reactive oxygen species levels. Consistent with the genetic interaction results, we also found reduced phosphorylation of Akt in DJ-1A RNAi animals, indicating an impairment of PI3K/Akt signaling by DJ-1A down-regulation, Together with recent findings in mammalian systems, these results implicate impairments of PI3K/Akt signaling and oxidative stress response in DJ-1-associated disease pathogenesis. We also observed impairment of PI3K/Akt signaling in the fly parkin model of PD, hinting at a common molecular event in the pathogenesis of PD. Manipulation of PI3K/Akt signaling may therefore offer therapeutic benefits for the treatment of PD.