Genetic analysis of KillerRed in <i>C. elegans</i> identifies a shared role of calcium genes in ROS-mediated neurodegeneration

In <i>C. elegans</i>, 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 <i>C. elegans</i> 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 <i>itr-1</i> (inositol trisphosphate receptor), <i>crt-1</i> (caltreticulin), and <i>unc-68</i> (ryanodine receptor) mutants. Similar to other neurotoxic conditions, neurodegeneration triggered by KillerRed was reduced in <i>itr-1</i> and <i>crt-1</i> mutants. Somewhat unexpectedly, genetic or pharmacological disruption of <i>unc-68</i> 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.