TDP-1/TDP-43 regulates stress signaling and age-dependent proteotoxicity in Caenorhabditis elegans.
TDP-1/TDP-43 regulates stress signaling and age-dependent proteotoxicity in Caenorhabditis elegans.
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DOI：
10.1371/journal.pgen.1002806
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发表时间：
2012-07
期刊：
影响因子：
4.5
通讯作者：
Parker JA
中科院分区：
文献类型：
--
作者：
Vaccaro A;Tauffenberger A;Ash PE;Carlomagno Y;Petrucelli L;Parker JA
TDP-43是一种多功能核酸结合蛋白，与肌萎缩侧索硬化症（ALS）和额颞叶痴呆等多种神经退行性疾病相关。为了更多地了解这种蛋白质的正常生物学和异常病理学作用，我们转向秀丽隐杆线虫及其直向同源物TDP-1。我们报道TDP-1在胰岛素/IGF通路中起作用，调节叉头转录因子fox 16/FOXO 3a下游的寿命和氧化应激反应。然而，尽管tdp-1突变体是应激敏感的，但tdp-1表达的慢性上调是有毒的，并会降低寿命。TDP-43或相关RNA结合蛋白FUS中的ALS相关突变激活未折叠蛋白反应并产生氧化应激，导致TDP-1表达的daf-16依赖性上调，对神经元功能和寿命产生负面影响。因此，内源性tdp-1的缺失挽救了突变体TDP-43和FUS在C.优雅的。这些结果表明，细胞应激对野生型TDP-1/TDP-43的慢性诱导可能会传播神经变性并缩短寿命。TAR DNA结合蛋白43（TDP-43）与几种人类年龄依赖性神经退行性疾病有关，但到目前为止，人们对TDP-43在衰老过程中的作用知之甚少。在这里，我们使用线虫秀丽隐杆线虫来研究TDP-43直向同源物TDP-1在衰老和神经变性中的作用。在这项研究中，我们发现TDP-1是一个应激反应基因，在胰岛素/IGF信号通路中起作用，以调节寿命和对氧化应激的反应。我们发现，虽然缺失tdp-1的蠕虫对压力敏感，但tdp-1的表达升高是有毒的。我们询问tdp-1是否也对肌萎缩侧索硬化症（ALS）中发现的毒性蛋白质引起的应激反应。使用ALS的蠕虫模型，我们发现突变TDP-43产生氧化应激并诱导TDP-1表达，对神经元功能和寿命产生负面影响。因此，去除TDP-1在我们的蠕虫ALS模型中挽救了毒性。TDP-1在细胞应激反应中的作用可能反映了处理不利环境条件的古老适应，其被导致蛋白毒性和氧化应激的基因突变不适当地激活和维持。我们预测，类似的机制可能存在于人类中，这有助于解释TDP-43参与越来越多的神经退行性疾病。TAR DNA结合蛋白43（TDP-43）与几种人类年龄依赖性神经退行性疾病有关，但到目前为止，人们对TDP-43在衰老过程中的作用知之甚少。在这里，我们使用线虫秀丽隐杆线虫来研究TDP-43直向同源物TDP-1在衰老和神经变性中的作用。在这项研究中，我们发现TDP-1是一个应激反应基因，在胰岛素/IGF信号通路中起作用，以调节寿命和对氧化应激的反应。我们发现，虽然缺失tdp-1的蠕虫对压力敏感，但tdp-1的表达升高是有毒的。我们询问tdp-1是否也对肌萎缩侧索硬化症（ALS）中发现的毒性蛋白质引起的应激反应。使用ALS的蠕虫模型，我们发现突变TDP-43产生氧化应激并诱导TDP-1表达，对神经元功能和寿命产生负面影响。因此，去除TDP-1在我们的蠕虫ALS模型中挽救了毒性。TDP-1在细胞应激反应中的作用可能反映了处理不利环境条件的古老适应，其被导致蛋白毒性和氧化应激的基因突变不适当地激活和维持。我们预测，类似的机制可能存在于人类中，这有助于解释TDP-43参与越来越多的神经退行性疾病。
TDP-43 is a multifunctional nucleic acid binding protein linked to several neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia. To learn more about the normal biological and abnormal pathological role of this protein, we turned to Caenorhabditis elegans and its orthologue TDP-1. We report that TDP-1 functions in the Insulin/IGF pathway to regulate longevity and the oxidative stress response downstream from the forkhead transcription factor DAF-16/FOXO3a. However, although tdp-1 mutants are stress-sensitive, chronic upregulation of tdp-1 expression is toxic and decreases lifespan. ALS–associated mutations in TDP-43 or the related RNA binding protein FUS activate the unfolded protein response and generate oxidative stress leading to the daf-16–dependent upregulation of tdp-1 expression with negative effects on neuronal function and lifespan. Consistently, deletion of endogenous tdp-1 rescues mutant TDP-43 and FUS proteotoxicity in C. elegans. These results suggest that chronic induction of wild-type TDP-1/TDP-43 by cellular stress may propagate neurodegeneration and decrease lifespan. TAR DNA Binding Protein 43 (TDP-43) is implicated in several human age-dependent neurodegenerative disorders, but until now little was known about TDP-43's role in the aging process. Here we used the nematode Caenorhabditis elegans to study the role of the TDP-43 orthologue tdp-1 in aging and neurodegeneration. In this study we discovered that tdp-1 is a stress-responsive gene acting within the Insulin/IGF signaling pathway to regulate lifespan and the response to oxidative stress. We found that, although worms missing tdp-1 were stress-sensitive, elevated expression of tdp-1 was toxic. We asked if tdp-1 also responded to the stress caused by toxic proteins found in Amyotrophic Lateral Sclerosis (ALS). Using worm models for ALS, we discovered that mutant TDP-43 generated oxidative stress and induced tdp-1 expression with negative consequences on neuronal function and lifespan. Consistently, removing tdp-1 rescued toxicity in our worm ALS models. tdp-1's role in the cellular stress response likely reflects an ancient adaptation to deal with unfavorable environmental conditions that is inappropriately activated and maintained by genetic mutations leading to proteotoxic and oxidative stress. We predict that similar mechanisms may exist in humans, helping explain the involvement of TDP-43 in a growing number of neurodegenerative disorders. TAR DNA Binding Protein 43 (TDP-43) is implicated in several human age-dependent neurodegenerative disorders, but until now little was known about TDP-43's role in the aging process. Here we used the nematode Caenorhabditis elegans to study the role of the TDP-43 orthologue tdp-1 in aging and neurodegeneration. In this study we discovered that tdp-1 is a stress-responsive gene acting within the Insulin/IGF signaling pathway to regulate lifespan and the response to oxidative stress. We found that, although worms missing tdp-1 were stress-sensitive, elevated expression of tdp-1 was toxic. We asked if tdp-1 also responded to the stress caused by toxic proteins found in Amyotrophic Lateral Sclerosis (ALS). Using worm models for ALS, we discovered that mutant TDP-43 generated oxidative stress and induced tdp-1 expression with negative consequences on neuronal function and lifespan. Consistently, removing tdp-1 rescued toxicity in our worm ALS models. tdp-1's role in the cellular stress response likely reflects an ancient adaptation to deal with unfavorable environmental conditions that is inappropriately activated and maintained by genetic mutations leading to proteotoxic and oxidative stress. We predict that similar mechanisms may exist in humans, helping explain the involvement of TDP-43 in a growing number of neurodegenerative disorders.
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