title: Prion-induced activation of cholesterogenic gene expression by Srebp2 in neuronal cells.
abstract: 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.
authors.affiliation: Institute of Virology, Technische Universität München, Trogerstrasse 30, 81675 Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Bach
authors.forename: Sabine
authors.initials: S
authors.lastname: Gilch
authors.forename: Romina
authors.initials: R
authors.lastname: Rost
authors.forename: Alex D
authors.initials: AD
authors.lastname: Greenwood
authors.forename: Marion
authors.initials: M
authors.lastname: Horsch
authors.forename: Glaucia N M
authors.initials: GN
authors.lastname: Hajj
authors.forename: Susanne
authors.initials: S
authors.lastname: Brodesser
authors.forename: Axel
authors.initials: A
authors.lastname: Facius
authors.forename: Sandra
authors.initials: S
authors.lastname: Schädler
authors.forename: Konrad
authors.initials: K
authors.lastname: Sandhoff
authors.forename: Johannes
authors.initials: J
authors.lastname: Beckers
authors.forename: Christine
authors.initials: C
authors.lastname: Leib-Mösch
authors.forename: Hermann M
authors.initials: HM
authors.lastname: Schätzl
authors.forename: Ina
authors.initials: I
authors.lastname: Vorberg
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002784:Cholesterol / Q000096:biosynthesis*; D015870:Gene Expression; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism*; D017096:Prion Diseases / Q000235:genetics* / Q000378:metabolism; D011328:Prions / Q000235:genetics / Q000378:metabolism*; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D011328:Prions; D051782:Sterol Regulatory Element Binding Protein 2; D002784:Cholesterol