Berger A J, Hart A C, Kaplan J M
Department of Genetics, Harvard Medical School, Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
J Neurosci. 1998 Apr 15;18(8):2871-80. doi: 10.1523/JNEUROSCI.18-08-02871.1998.
We describe a genetic model for neurodegeneration in the nematode Caenorhabditis elegans. Constitutive activation of the GTP-binding protein Galphas 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 Galphas-induced cytotoxicity, ranging from 0 to 88% of cells affected. Mutations that prevent programmed cell death do not prevent Galphas-induced killing, suggesting that these deaths do not occur by apoptosis. Mutations in three genes protect against Galphas-induced cell deaths. The acy-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 Galphas. These experiments define an intracellular signaling cascade that triggers a necrotic form of neurodegeneration.
我们描述了线虫秀丽隐杆线虫神经退行性变的遗传模型。GTP结合蛋白Gαs的组成型激活会诱导神经退行性变。神经元丧失分两个阶段发生，在此过程中，受影响的细胞在幼虫早期会经历肿胀反应，并随后在幼虫发育的某个阶段死亡。不同类型的神经细胞对Gαs诱导的细胞毒性的敏感性差异很大，受影响细胞的比例从0%到88%不等。阻止程序性细胞死亡的突变并不能防止Gαs诱导的细胞死亡，这表明这些死亡并非通过凋亡发生。三个基因的突变可防止Gαs诱导的细胞死亡。acy-1基因对于神经退行性变是绝对必需的，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诱导的神经退行性变是由第二信使cAMP介导的。unc-36和eat-4基因的突变具有部分神经保护作用，这表明内源性信号传导可调节Gαs神经毒性作用的严重程度。这些实验确定了一个触发坏死性神经退行性变形式的细胞内信号级联反应。
