Role of Prion Protein Accumulation in Lipid Rafts During Aging

Prion diseases are a family of fatal neurodegenerative disorders characterized mainly by spongiform degeneration and widespread neuronal loss. In humans, the vast majority of cases are sporadic and the average age of onset is around 65. The event triggering the pathogenesis is the conversion of the cellular prion protein (PrPC) to a β-rich isoform (PrPSc) and several studies clearly demonstrated lipid rafts involvement in this conformational transition. In the aging brain — where sporadic diseases predominantly arise — alterations in major components of lipid rafts, such as cholesterol and sphingolipids, have already been shown. Based on these premises, we decided to investigate the conditions whereby sporadic diseases may develop, focusing our attention on the cell membrane of neurons in aging brains. By comparing the membrane compartmentalization of PrPC in hippocampal neuronal cells of young with aging mice, we observed an accumulation of this protein in lipid rafts of old mice. We also showed that modifications of sphingomyelin content in cellular membrane could trigger the accumulation of PrPC in lipid rafts. Ultimately, we observed that lowering sphingolipids in prion-infected cells led to a decrease in PrPSc levels. Our results indicate that the aging process, which is accompanied by changes in the lipidic composition of the neuronal membrane, can modify the compartmentalization of PrPC. This might contribute to the appearance of the sporadic form of prion diseases in aged population.