Ferroptosis-related mechanisms in prion diseases provide insights into neurodegeneration and reveal therapeutic implications

Abstract

Prion diseases are a group of fatal neurodegenerative disorders caused by misfolded proteins. Understanding the regulatory networks of ferroptosis in prion diseases could unveil new diagnostic and therapeutic strategies. To explore this, we systematically evaluated ferroptosis-associated alterations across human sporadic Creutzfeldt–Jakob disease (sCJD) brain samples, the ME7-infected mouse model, and in vitro using PrP 106-126 -treated SH-SY5Y cells. In sCJD patients, we observed a significant decrease in GPX4 expression, accompanied by elevated lipid peroxidation, as confirmed by malondialdehyde assays. Furthermore, in vitro experiments using PrP 106-126 -treated cells confirmed that ferroptosis-related mechanisms actively contribute to cell death, characterized by elevated lipid peroxidation, reactive oxygen species, and increased intracellular Fe 2+ levels, as well as diminished glutathione activity. Critically, pharmacological inhibition with ferrostatin-1 effectively mitigated this neurotoxicity, consistent with a ferroptosis-related mechanism. To validate these findings in vivo , we demonstrated that ME7-infected mice exhibited significantly lower levels of GPX4 and SLC7A11, which correlated with increased 4-hydroxynonenal and neuronal damage. Finally, bioinformatic analysis of the GSE124571 dataset identified a distinct transcriptomic signature of 130 differentially expressed ferroptosis-related genes in sCJD patients. These results collectively suggest that ferroptosis-associated alterations are involved in prion-associated neurodegeneration, offering valuable pathophysiological insights into disease progression. • Ferroptosis-related stress markers are observed in human sCJD and ME7 mouse brains • GPX4 depletion and lipid peroxidation mark the pathological landscape of sCJD • Ferrostatin-1 rescues PrP 106-126 -induced neurotoxicity and oxidative stress in vitro • Reduced GPX4 expression correlates with neuronal damage in ME7-infected mice • Transcriptomics reveals dysregulation of ferroptosis-related pathways in sCJD