Diapause formation and downregulation of insulin-like signaling via DAF-16/FOXO delays axonal degeneration and neuronal loss.
Diapause formation and downregulation of insulin-like signaling via DAF-16/FOXO delays axonal degeneration and neuronal loss.
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DOI：
10.1371/journal.pgen.1003141
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Court FA
中科院分区：
文献类型：
--
作者：
Calixto A;Jara JS;Court FA
轴突变性是神经退行性疾病发病机制中的关键事件。我们在这里表明，mec-4d触发秀丽隐杆线虫神经元和哺乳动物轴突的轴突变性具有机械相似性，因为两者都通过抑制钙增加、线粒体功能障碍和NMNAT过表达而获救。然后我们探讨活性氧（ROS）是否参与轴突变性和神经元死亡。秀丽隐杆线虫具有增强的抗活性氧系统，并且mec-4d蠕虫完全免受轴突变性和神经元丢失的保护。从机制上讲，胰岛素/ igf -1样信号通路的下调以DAF-16/ foxo依赖的方式保护神经元免于退化，并与超氧化物歧化酶和过氧化氢酶的表达增加有关。热量限制和全身抗氧化处理可减少氧化损伤，保护秀丽隐杆线虫轴突免受mec-4d介导的变性，并延缓小鼠沃勒氏变性。总之，我们发现IIS通路在促退行性刺激下维持神经元稳态至关重要，并确定ROS是体内神经元退行性变的关键中间体。由于轴突变性是神经退行性疾病的早期病理事件，我们的工作确定了以轴突丧失和功能损伤为特征的几种疾病的治疗干预的潜在目标。轴突变性和神经元丢失被认为是神经退行性疾病的重要病理因素。因此，延迟或阻断这些过程是神经保护的关键。在这项工作中，我们使用了一种结合无脊椎动物（秀丽隐杆线虫）和脊椎动物（小鼠）模型系统的体内方法，以确定轴突变性机制中一个新的和意想不到的参与者。在这里，我们证明了神经元体细胞和轴突都是通过依赖于氧化应激的步骤退化的，这一步骤可以通过控制氧化应激抵抗途径的遗传下调有效地延迟。令人印象深刻的是，我们发现滞育的形成，这是一种与冬眠条件相关的状态，完全阻止了神经元的变性。我们发现了与轴突变性相关的几种疾病（如多发性硬化症、运动神经元和帕金森病）有关的神经元退行性机制的新参与者，为神经保护提供了新的潜在靶点。
Axonal degeneration is a key event in the pathogenesis of neurodegenerative conditions. We show here that mec-4d triggered axonal degeneration of Caenorhabditis elegans neurons and mammalian axons share mechanistical similarities, as both are rescued by inhibition of calcium increase, mitochondrial dysfunction, and NMNAT overexpression. We then explore whether reactive oxygen species (ROS) participate in axonal degeneration and neuronal demise. C. elegans dauers have enhanced anti-ROS systems, and dauer mec-4d worms are completely protected from axonal degeneration and neuronal loss. Mechanistically, downregulation of the Insulin/IGF-1-like signaling (IIS) pathway protects neurons from degenerating in a DAF-16/FOXO–dependent manner and is related to superoxide dismutase and catalase-increased expression. Caloric restriction and systemic antioxidant treatment, which decrease oxidative damage, protect C. elegans axons from mec-4d-mediated degeneration and delay Wallerian degeneration in mice. In summary, we show that the IIS pathway is essential in maintaining neuronal homeostasis under pro-degenerative stimuli and identify ROS as a key intermediate of neuronal degeneration in vivo. Since axonal degeneration represents an early pathological event in neurodegeneration, our work identifies potential targets for therapeutic intervention in several conditions characterized by axonal loss and functional impairment. Axonal degeneration and neuronal loss are currently considered crucial pathological factors in neurodegenerative diseases. Therefore, delaying or blocking these procesess is key for neuroprotection. In this work, we used an in vivo approach combining invertebrate (C. elegans) and vertebrate (mice) model systems to identify a novel and unexpected player in the mechanisms of axonal degeneration. Here, we demonstrate that both neuronal somas and axons degenerate through a step dependent on oxidative stress that can be efficiently delayed by genetic downregulation of a pathway controlling oxidative stress resistance. Impressively, we discovered that diapause formation, which is a state related to hibernating conditions, fully prevents neuronal degeneration. We uncovered new players in the degenerative mechanisms of neurons with relevance for several conditions associated to axonal degeneration, such as multiple sclerosis, motoneuron, and Parkinson diseases, offering novel potential targets for neuroprotection.
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影响因子：
15.8
作者：
Civitarese AE;Carling S;Heilbronn LK;Hulver MH;Ukropcova B;Deutsch WA;Smith SR;Ravussin E;CALERIE Pennington Team
通讯作者：
CALERIE Pennington Team
DOI：
10.1073/pnas.0610877104
发表时间：
2007-02-13
影响因子：
11.1
作者：
Chelur, Dattananda S.;Chalfie, Martin
通讯作者：
Chalfie, Martin
影响因子：
9.2
作者：
Ferri, A;Sanes, JR;Kato, AC
通讯作者：
Kato, AC
影响因子：
56.9
作者：
Arantes-Oliveira, N;Apfeld, J;Kenyon, C
通讯作者：
Kenyon, C
影响因子：
9
作者：
Ehrenfried, JA;Evers, BM;Thompson, JC
通讯作者：
Thompson, JC