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Genes contributing to prion pathogenesis

Patrick Tremblay^1,2,

Fruma Yehiely^1,

Carsten Korth^1,

Pauline M. Rudd^7,

Tracey Dawson Cruz^10,

William A. Kuziel^10,

¹ Institute for Neurodegenerative Diseases, University of California, San Francisco, CA, USA
² Department of Neurology, University of California, San Francisco, CA, USA
³ Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA
⁴ INSERM, U602, and Université Paris 11, Villejuif, France
⁵ Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA
⁶ Muscular and Neurodegenerative Disease Unit, University of Genova and G. Gaslini Pediatric Institute, Genova, Italy
⁶ Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
⁷ Department of Biochemistry and Oxford Glycobiology Institute, University of Oxford, Oxford, UK
⁸ Department of Pharmacology and Toxicology, University of Kansas, Lawrence, KS, USA
⁹ Institute for Human Genetics and Department of Pediatrics, University of California, San Francisco, CA, USA
¹⁰ Department of Pathology and Laboratory Medicine, University of North Carolina Medical Center, Chapel Hill, NC, USA
¹¹ Biotechnology Research and Innovation Center, Faculty of Health Sciences, University of Copenhagen, Denmark
¹² Departments of Neurology, Neuroscience and Graduate Program in Neuroscience, University of Minnesota, and Geriatric Research, Education and Clinical Center, Minneapolis Veterans Affairs Medical Center, Minneapolis, MN, USA
¹³ McLaughlin Research Institute, Great Falls, MT, USA
¹⁴ Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
¹⁵ Geriatric Research, Education and Clinical Center, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA
¹⁶ Neuroscience Graduate Program, University of California, San Francisco, CA, USA
¹⁷ Gladstone Institute of Neurological Disease, University of California, San Francisco, CA, USA
¹⁸ Cardiovascular Research Institute and Departments of Medicine and Pathology, University of California, San Francisco, CA, USA
¹⁹ Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA, USA

Correspondence
Stanley B. Prusiner
stanley{at}ind.ucsf.edu

Prion diseases are caused by conversion of a normally folded, non-pathogenic isoform of the prion protein (PrP^C) to a misfolded, pathogenic isoform (PrP^Sc). Prion inoculation experiments in mice expressing homologous PrP^C molecules on different genetic backgrounds displayed different incubation times, indicating that the conversion reaction may be influenced by other gene products. To identify genes that contribute to prion pathogenesis, we analysed incubation times of prions in mice in which the gene product was inactivated, knocked out or overexpressed. We tested 20 candidate genes, because their products either colocalize with PrP, are associated with Alzheimer's disease, are elevated during prion disease, or function in PrP-mediated signalling, PrP glycosylation, or protein maintenance. Whereas some of the candidates tested may have a role in the normal function of PrP^C, our data show that many genes previously implicated in prion replication have no discernible effect on the pathogenesis of prion disease. While most genes tested did not significantly affect survival times, ablation of the amyloid beta (A4) precursor protein (App) or interleukin-1 receptor, type I (Il1r1), and transgenic overexpression of human superoxide dismutase 1 (SOD1) prolonged incubation times by 13, 16 and 19 %, respectively.

Present address: Pappas Ventures, Montreal, QC H3A 1X6, Canada.

Present address: Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, USA.

Present address: Institute for Neuropathology, Heinrich Heine University Düsseldorf, 40001 Düsseldorf, Germany.

||Present address: Department of Genetics and Genomics, Roslin Institute, Roslin, Midlothian EH25 9PS, Scotland, UK.

¶Present address: Department of Biochemistry, Neurobiochemistry, Ludwig Maximilians University, Munich, Germany.

#Present address: University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

Present address: Dublin-Oxford Glycobiology Laboratory, University College, Belfield, Dublin 4, Ireland.

Present address: Departments of Forensic Science and Biology, Virginia Commonwealth University, Richmond, VA 23284-3079, USA.

Present address: PDL BioPharma, Inc., Redwood City, CA 94063, USA.

||||Present address: Center for Human Genetics, K.U. Leuven, Department of Molecular and Developmental Genetics, 3000 Leuven, Belgium.

Supplementary material is available with the online version of this paper.

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