Young Lyndsay E A, Shoben Chelsea, Ricci Kyra, Williams Daniel C
a Department of Biology , Coastal Carolina University , Conway , SC , USA.
J Neurogenet. 2019 Mar;33(1):1-9. doi: 10.1080/01677063.2018.1531857. Epub 2018 Nov 29.
In C. elegans, neurodegeneration induced by excitotoxicity or aggregation of misfolded proteins is dependent on genes involved in calcium release from the endoplasmic reticulum. Reactive oxygen species (ROS) can also induce neurodegeneration, but the relationship between ROS-mediated neurodegeneration and calcium has not been established. We activated KillerRed in the GABA neurons of C. elegans to produce ROS that leads to functional loss and structural degeneration of these neurons and demonstrated that the severity of neurodegeneration was dependent on extent of KillerRed activation. To genetically examine the role of calcium in ROS-mediated neurodegeneration, we measured functional neurodegeneration in itr-1 (inositol trisphosphate receptor), crt-1 (caltreticulin), and unc-68 (ryanodine receptor) mutants. Similar to other neurotoxic conditions, neurodegeneration triggered by KillerRed was reduced in itr-1 and crt-1 mutants. Somewhat unexpectedly, genetic or pharmacological disruption of unc-68 had a minimal effect on neurodegeneration. Our results indicate ROS-mediated neurodegeneration occurs through a conserved calcium regulated mechanism and suggest that components of the degeneration process have different sensitivities to ROS.
在秀丽隐杆线虫中，由兴奋性毒性或错误折叠蛋白聚集诱导的神经退行性变依赖于参与内质网钙释放的基因。活性氧（ROS）也可诱导神经退行性变，但ROS介导的神经退行性变与钙之间的关系尚未明确。我们在秀丽隐杆线虫的GABA神经元中激活了KillerRed以产生ROS，导致这些神经元功能丧失和结构退化，并证明神经退行性变的严重程度取决于KillerRed的激活程度。为了从遗传学角度研究钙在ROS介导的神经退行性变中的作用，我们检测了肌醇三磷酸受体（itr-1）、钙网蛋白（crt-1）和兰尼碱受体（unc-68）突变体中的功能性神经退行性变。与其他神经毒性情况类似，itr-1和crt-1突变体中由KillerRed触发的神经退行性变有所减轻。有点出乎意料的是，unc-68的基因或药理学破坏对神经退行性变的影响最小。我们的结果表明，ROS介导的神经退行性变通过一种保守的钙调节机制发生，并提示退变过程的组成部分对ROS具有不同的敏感性。
