Prion diseases are
neurodegenerative diseases associated with the accumulation of a pathogenic
isoform of the host-encoded
prion protein. The cellular responses to
prion infection are not well defined. By performing microarray analysis on cultured neuronal cells infected with
prion strain 22L, in the group of up-regulated genes we observed predominantly genes of the
cholesterol pathway. Increased transcript levels of at least nine
enzymes involved in
cholesterol synthesis, including the gene for the rate-limiting
hydroxymethylglutaryl-CoA reductase, were detected. Up-regulation of cholesterogenic genes was attributable to a
prion-dependent increase in the amount and activity of the
sterol regulatory element-binding protein Srebp2, resulting in elevated levels of total and free cellular
cholesterol. The up-regulation of
cholesterol biosynthesis appeared to be a characteristic response of neurons to
prion challenge, as cholesterogenic transcripts were also elevated in persistently infected GT-1 cells and
prion-exposed primary hippocampal neurons but not in microglial cells and primary astrocytes. These results convincingly demonstrate that
prion propagation not only depends on the availability of
cholesterol but that neuronal cells themselves respond to
prions with specific up-regulation of
cholesterol biosynthesis.