Redox mechanisms and their pathological role in prion diseases: The road to ruin

Abstract

Prion diseases, also known as transmissible spongiform encephalopathies, are rare, progressive, and fatal neurodegenerative disorders, which are caused by the accumulation of the misfolded cellular prion protein (PrPC). The resulting cytotoxic prion species, referred to as the scrapie prion isoform (PrPSc), assemble in aggregates and interfere with neuronal pathways, ultimately rendering neurons dysfunctional. As the prion protein physiologically interacts with redox-active metals, an altered redox balance within the cell can impact these interactions, which may lead to and facilitate further misfolding and aggregation. The initiation of misfolding and the aggregation processes will, in turn, induce microglial activation and neuroinflammation, which leads to an imbalance in cellular redox homeostasis and enhanced redox stress. Potential approaches for therapeutics target redox signalling, and this review illustrates the pathways involved in the above processes.

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 (PrP^C), which facilitates conversion to the disease isoform (PrP^Sc), further promoting disease progression.