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的蛋白质聚集引起的神经变性取决于内质网中钙释放的相关基因。活性氧（ROS）也可以诱发神经变性，但ROS介导的神经变性与钙之间的关系尚未建立。我们在秀丽隐杆线虫的GABA神经元中激活了KillerRed，以产生导致这些神经元功能丧失和结构变性的ROS，并证明了神经变性的严重程度取决于KillerRed激活的程度。为了从基因上检查钙在ROS介导的神经变性中的作用，我们测量了itr-1（肌醇三磷酸受体）中的功能性神经变性，crt-1（钙网蛋白）和unc-68（ryanodine受体）突变体。与其他神经毒性疾病类似，由杀手红触发的神经变性在itr-1和crt-1突变体中减少。出乎意料的是，unc-68的遗传或药理学破坏对神经变性的影响很小。我们的结果表明ROS介导的神经变性是通过保守的钙调节机制发生的，表明该变性过程的成分对ROS的敏感性不同。