Royal Veterinary College researchers report that prion infection of neurons increases the free cholesterol content in cell membranes. They suggest that this disturbance in membrane cholesterol may be the mechanism by which prions cause neurodegeneration.
The investigators compared the amounts of protein and cholesterol in prion-infected neuronal cell lines and primary cortical neurons with uninfected controls. Protein levels were similar across the cells, but the amount of total cholesterol, a mixture of free and esterified cholesterol, was significantly higher in the infected cell lines. The team found that the cholesterol balance was also affected. The amount of free cholesterol increased, but that of cholesterol esters was reduced.
The scientists attempted to reproduce the effects of prions on cholesterol levels by stimulating cholesterol biosynthesis or by adding exogenous cholesterol. Both approaches, however, resulted in increased amounts of cholesterol esters but not of free cholesterol.
Free cholesterol is thought to affect the function of the cell membranes and to lead to abnormal activation of phospholipase A2, an enzyme implicated in the depletion of neurons in prion and Alzheimer’s disease.
The study is published in the online open access journal BMC Biology.