Journal of Biological Chemistry
Volume 284, Issue 45, 6 November 2009, Pages 31260-31269
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Lipids and Lipoproteins: Metabolism, Regulation, and Signaling
Prion-induced Activation of Cholesterogenic Gene Expression by Srebp2 in Neuronal Cells*

https://doi.org/10.1074/jbc.M109.004382Get rights and content
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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.

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*

This work was supported by Deutsche Forschungsgemeinschaft Grants VO 1277/1-2, SFB 596 (Projects A8 and B14), by Bayerischer Forschungsverbund FORPRION (TUM 7), and by the European Commission Grant TSEUR LSHB-CT-2005-018805. This study was performed within the framework of EU FP6 Network of Excellence Neuroprion.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–3 and Tables 1 and 2.

1

Present address: Leibnitz Instítute for zoo- and Wildlife Research, Alfred-Kowalke Str. 17, 10315 Berlin, Germany.

2

Present address: CECAD Cologne, Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Goldenfelsstr. 19-21, 50935 Cologne, Germany.

3

Present address: Nycomed GmbH, Pharmacometrics, Byk Gulden Str. 2, 78467 Konstanz, Germany.