Small heat shock proteins mediate cell-autonomous and -nonautonomous protection in a Drosophila model for environmental-stress-induced degeneration.
Small heat shock proteins mediate cell-autonomous and -nonautonomous protection in a Drosophila model for environmental-stress-induced degeneration.
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DOI：
10.1242/dmm.026385
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发表时间：
2016-09-01
影响因子：
4.3
通讯作者：
Ordway RW
中科院分区：
文献类型：
--
作者：
Kawasaki F;Koonce NL;Guo L;Fatima S;Qiu C;Moon MT;Zheng Y;Ordway RW
细胞和组织的退化以及退行性疾病的发展受到遗传和环境因素的影响，这些因素影响蛋白质的错误折叠和蛋白质毒性。为了更好地了解环境在果蝇退化中的作用，我们开发了一个热休克(HS)应激诱导果蝇退化的遗传模型。这个模型展示了一种独特的特征组合，增强了对退化和涉及环境压力的保护机制的遗传分析。这些包括针对特定细胞类型的蛋白平衡和变性对全球压力的响应，在一个简单和可访问的敏感细胞类型网络中的细胞-非自治相互作用，以及对退化诱导的精确时间控制。在野生型果蝇中，HS应激导致飞行能力的选择性丧失和组成飞行运动的三种敏感细胞类型的退化：肌肉、运动神经元和相关的胶质细胞。其他运动行为持续存在，因此，控制腿部运动功能的相应细胞类型抵抗退化。以弥漫性泛素化蛋白聚集体为特征的肌肉蛋白平衡失败是飞行马达退变的先兆。此外，肌肉特异性过表达一种小的热休克蛋白(HSP23)，促进蛋白稳定，保护肌肉免受HS应激的影响。值得注意的是，神经元和胶质细胞也受到了保护，这表明一个小的HSP可以介导细胞非自主保护。对肌肉的细胞自主保护以泛素化蛋白的独特分布为特征，包括核周定位和清除与核周微管网络相关的蛋白质聚集体。这一网络在变性前的野生型制剂中被严重破坏，表明它在肌肉蛋白平衡和保护方面发挥着重要作用。最后，对具有抵抗力的腿部肌肉的研究表明，在HS应激后，它们维持着蛋白稳定和微管细胞骨架。这些发现为涉及环境因素贡献的退化和保护机制的遗传分析建立了模型，并促进了我们对小分子热休克蛋白的保护功能和治疗潜力的理解。摘要：环境应激诱导的果蝇退化模型为退行性疾病机制的遗传分析显示了关键特征，并揭示了由小分子热休克蛋白介导的新的保护形式。
Cell and tissue degeneration, and the development of degenerative diseases, are influenced by genetic and environmental factors that affect protein misfolding and proteotoxicity. To better understand the role of the environment in degeneration, we developed a genetic model for heat shock (HS)-stress-induced degeneration in Drosophila. This model exhibits a unique combination of features that enhance genetic analysis of degeneration and protection mechanisms involving environmental stress. These include cell-type-specific failure of proteostasis and degeneration in response to global stress, cell-nonautonomous interactions within a simple and accessible network of susceptible cell types, and precise temporal control over the induction of degeneration. In wild-type flies, HS stress causes selective loss of the flight ability and degeneration of three susceptible cell types comprising the flight motor: muscle, motor neurons and associated glia. Other motor behaviors persist and, accordingly, the corresponding cell types controlling leg motor function are resistant to degeneration. Flight motor degeneration was preceded by a failure of muscle proteostasis characterized by diffuse ubiquitinated protein aggregates. Moreover, muscle-specific overexpression of a small heat shock protein (HSP), HSP23, promoted proteostasis and protected muscle from HS stress. Notably, neurons and glia were protected as well, indicating that a small HSP can mediate cell-nonautonomous protection. Cell-autonomous protection of muscle was characterized by a distinct distribution of ubiquitinated proteins, including perinuclear localization and clearance of protein aggregates associated with the perinuclear microtubule network. This network was severely disrupted in wild-type preparations prior to degeneration, suggesting that it serves an important role in muscle proteostasis and protection. Finally, studies of resistant leg muscles revealed that they sustain proteostasis and the microtubule cytoskeleton after HS stress. These findings establish a model for genetic analysis of degeneration and protection mechanisms involving contributions of environmental factors, and advance our understanding of the protective functions and therapeutic potential of small HSPs. Summary: A Drosophila model for environmental-stress-induced degeneration exhibits key features for genetic analysis of degenerative disease mechanisms and reveals new forms of protection mediated by small heat shock proteins.
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影响因子：
3.8
作者：
Cannon, Jason R.;Greenamyre, J. Timothy
通讯作者：
Greenamyre, J. Timothy
DOI：
10.1073/pnas.152330499
发表时间：
2002-12-10
影响因子：
11.1
作者：
Bonini, NM
通讯作者：
Bonini, NM
影响因子：
5.3
作者：
Kawasaki, F;Zou, BY;Ordway, RW
通讯作者：
Ordway, RW
影响因子：
11.2
作者：
Blumen, Sergiu C.;Astord, Stephanie;Viollet, Louis
通讯作者：
Viollet, Louis
DOI：
10.1016/j.biocel.2012.02.022
发表时间：
2012-10-01
影响因子：
4
作者：
Garrido, C.;Paul, C.;Kampinga, H. H.
通讯作者：
Kampinga, H. H.