Fig 1.
Hallmarks of prion disease pathogenesis include neuroinflammation and mitochondrial dysfunction, which facilitate production of reactive oxygen and nitrogen species via inflammatory-related enzymes including NADPH-oxidase (Nox) and inducible nitric oxide synthase (iNOS).
These produce radical species such as superoxide (O2.-) and nitric oxide (NO.), respectively. Under normal conditions, antioxidants such as superoxide dismutase (SOD) would neutralise these radicals to less reactive species or reduce them to water. However, in pathological conditions such as prion disease where oxidant production is favoured, antioxidants are overwhelmed, which results in cellular redox stress. This is further exacerbated by the mobilisation of redox-active and transition metals such as iron (Fe2+), zinc (Zn2+), copper (Cu2+), and manganese (Mn2+), which causes dyshomeostasis in cellular biometal distribution through various divalent metal transporters (ZnT1, ZIP, DMT, ATP7B) and promotes oxidative stress. Together, these conditions may favour glycosylation of the native prion protein (PrPC), which facilitates conversion to the disease isoform (PrPSc), further promoting disease progression.