Opposing roles of p38 and JNK in a Drosophila model of TDP-43 proteinopathy reveal oxidative stress and innate immunity as pathogenic components of neurodegeneration.
Opposing roles of p38 and JNK in a Drosophila model of TDP-43 proteinopathy reveal oxidative stress and innate immunity as pathogenic components of neurodegeneration.
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DOI：
10.1093/hmg/ddu493
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发表时间：
2015-02
影响因子：
3.5
通讯作者：
Lihong Zhan;Qijing Xie;R. Tibbetts
中科院分区：
文献类型：
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作者：
Lihong Zhan;Qijing Xie;R. Tibbetts
43 kDa TAR DNA结合蛋白（TDP-43）的病理聚集和突变与肌萎缩侧索硬化和额颞叶变性的发病机制密切相关。TDP-43神经毒性已在小鼠、斑马鱼、秀丽隐杆线虫和果蝇中广泛建模，其中TDP-43在运动神经元中的选择性表达导致麻痹和过早致死。通过对TDP-43的遗传修饰基因的筛选，我们发现果蝇双亮氨酸激酶Wallenda（Wnd）及其下游激酶JNK和p38影响TDP-43的神经毒性。减少Wnd基因剂量或过表达其拮抗剂highwire部分挽救了TDP-43相关的过早致死性。在Wnd下游，JNK和p38激酶在TDP-43相关的神经变性中发挥相反的作用。p38 b基因的LOF等位基因以及p38抑制剂减少了TDP-43相关的过早致死性，而p38 b GOF导致表型恶化。与此形成鲜明对比的是，破坏性等位基因篮（Bsk），果蝇同源的JNK，加剧寿命缩短，而过表达的Bsk延长寿命。在可能的机制中，我们发现运动神经元定向表达TDP-43引起氧化应激和先天免疫基因激活，分别由p38 GOF和Bsk LOF加剧。先天免疫在TDP-43相关神经变性中的关键病理作用进一步得到以下发现的支持：Toll/Dif和Imd/Relish炎症途径的遗传抑制显著延长了TDP-43转基因果蝇的寿命。我们认为氧化应激和神经炎症是TDP-43相关神经变性的内在组成部分，细胞保护性JNK和细胞毒性p38信号传导之间的平衡决定了果蝇TDP-43表达的表型结果。
Pathological aggregation and mutation of the 43-kDa TAR DNA-binding protein (TDP-43) are strongly implicated in the pathogenesis amyotrophic lateral sclerosis and frontotemporal lobar degeneration. TDP-43 neurotoxicity has been extensively modeled in mice, zebrafish, Caenorhabditis elegans and Drosophila, where selective expression of TDP-43 in motoneurons led to paralysis and premature lethality. Through a genetic screen aimed to identify genetic modifiers of TDP-43, we found that the Drosophila dual leucine kinase Wallenda (Wnd) and its downstream kinases JNK and p38 influenced TDP-43 neurotoxicity. Reducing Wnd gene dosage or overexpressing its antagonist highwire partially rescued TDP-43-associated premature lethality. Downstream of Wnd, the JNK and p38 kinases played opposing roles in TDP-43-associated neurodegeneration. LOF alleles of the p38b gene as well as p38 inhibitors diminished TDP-43-associated premature lethality, whereas p38b GOF caused phenotypic worsening. In stark contrast, disruptive alleles of Basket (Bsk), the Drosophila homologue of JNK, exacerbated longevity shortening, whereas overexpression of Bsk extended lifespan. Among possible mechanisms, we found motoneuron-directed expression of TDP-43 elicited oxidative stress and innate immune gene activation that were exacerbated by p38 GOF and Bsk LOF, respectively. A key pathologic role for innate immunity in TDP-43-associated neurodegeneration was further supported by the finding that genetic suppression of the Toll/Dif and Imd/Relish inflammatory pathways dramatically extended lifespan of TDP-43 transgenic flies. We propose that oxidative stress and neuroinflammation are intrinsic components of TDP-43-associated neurodegeneration and that the balance between cytoprotective JNK and cytotoxic p38 signaling dictates phenotypic outcome to TDP-43 expression in Drosophila.