Oxidative stress as a contributor to neuronal death during prion infection is supported by various oxidative damage markers accumulating in the brain during the course of disease. The cellular substrate of the causative agent, the prion protein, is also linked with protective functions against oxidative stress. Our previous work has found that in chronic prion infection an apoptotic sub-population of cells exhibit oxidative stress and accumulation of oxidised lipid and protein aggregates with caspase recruitment. Given the likely failure of antioxidant defence mechanisms within apoptotic prion-infected cells, we aimed to investigate the role of the critical antioxidant pathway components, superoxide dismutases (SOD) 1 and 2, in an in vitro model of chronic prion infection. Increased total SOD activity, attributable to SOD1, was found in the overall population coincident with a decrease in SOD2 protein levels. When apoptotic cells were separated from the total population, the induction of SOD activity in the infected apoptotic cells was lost with activity reduced back to levels seen in mock-infected control cells. In addition, mitochondrial superoxide production was increased and mitochondrial numbers decreased in the infected apoptotic sub-population. Further, a pan-caspase probe co-localised with SOD2 outside of mitochondria within cytosolic aggregates in infected cells and inhibition of caspase activity was able to restore cellular levels of SOD2 in the whole unseparated infected population to that of the mock-infected control cells. Our results suggest prion propagation exacerbates an apoptotic pathway whereby mitochondrial dysfunction follows mis-localisation of SOD2 to cytosolic caspases, permitting its degradation. Eventually cellular capacity to maintain oxidative homeostasis is overwhelmed, thus resulting in cell death.
- Received August 7, 2012.
- Accepted March 31, 2013.
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