Gαs-Induced Neurodegeneration inCaenorhabditis elegans
Gαs-Induced Neurodegeneration inCaenorhabditis elegans
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DOI：
10.1523/jneurosci.18-08-02871.1998
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发表时间：
1998-04
期刊：
影响因子：
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通讯作者：
A. Berger;A. Hart;J. M. Kaplan
中科院分区：
文献类型：
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作者：
A. Berger;A. Hart;J. M. Kaplan
我们描述了一个遗传模型的神经变性线虫线虫。GTP结合蛋白Gαs的组成性激活诱导神经变性。神经元损失发生在两个阶段，其中受影响的细胞在幼幼虫中经历肿胀反应，随后在幼虫发育期间的某个时间死亡。不同的神经细胞类型对Gα s诱导的细胞毒性的敏感性差异很大，从0到88%的细胞受到影响。阻止程序性细胞死亡的突变不能阻止Gα s诱导的杀伤，这表明这些死亡不是通过凋亡发生的。三个基因的突变可以防止Gα s诱导的细胞死亡。Theacy-1基因是神经退行性变所必需的，并且预测的ACY-1蛋白与哺乳动物腺苷酸环化酶高度相似（40%相同）。因此，GS诱导的神经变性是由第二信使cAMP介导的。unc-36和eat-4基因的突变具有部分神经保护作用，这表明内源性信号调节Gαs神经毒性作用的严重程度。这些实验定义了触发神经变性的坏死形式的细胞内信号级联。
We describe a genetic model for neurodegeneration in the nematodeCaenorhabditis elegans. Constitutive activation of the GTP-binding protein Gαs induces neurodegeneration. Neuron loss occurs in two phases whereby affected cells undergo a swelling response in young larvae and subsequently die sometime during larval development. Different neural cell types vary greatly in their susceptibility to Gαs-induced cytotoxicity, ranging from 0 to 88% of cells affected. Mutations that prevent programmed cell death do not prevent Gαs-induced killing, suggesting that these deaths do not occur by apoptosis. Mutations in three genes protect against Gαs-induced cell deaths. Theacy-1 gene is absolutely required for neurodegeneration, and the predicted ACY-1 protein is highly similar (40% identical) to mammalian adenylyl cyclases. Thus, Gs-induced neurodegeneration is mediated by the second messenger cAMP. Mutations in the unc-36 and eat-4 genes are partially neuroprotective, which indicates that endogenous signaling modulates the severity of the neurotoxic effects of Gαs. These experiments define an intracellular signaling cascade that triggers a necrotic form of neurodegeneration.