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

Abstract

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.

Keywords:

• C. elegans
• neurodegeneration
• reactive oxygen species
• calcium

Acknowledgements

The authors are grateful to Dr. Monica Driscoll for guidance and comments on this work.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work utilized strains provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). This publication was supported in part by grant P20GM103499 (SC-INBRE) from the National Institutes of General Medical Sciences, National Institutes of Health.